PAK2

Summary

PAK2 (p21 (RAC1) activated kinase 2, HGNC:8591) is a protein-coding gene on chromosome 3q29, encoding Serine/threonine-protein kinase PAK 2 (Q13177). Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation. It is a selective cancer dependency (DepMap: 12.9% of cell lines).

The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell.

Source: NCBI Gene 5062 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Knobloch syndrome 2 (Strong, GenCC)
• GWAS associations: 24
• Clinical variants (ClinVar): 82 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 41
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 12.9% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity little evidence
• MANE Select transcript: NM_002577

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8591
Approved symbol	PAK2
Name	p21 (RAC1) activated kinase 2
Location	3q29
Locus type	gene with protein product
Status	Approved
Aliases	PAK65, PAKgamma
Ensembl gene	ENSG00000180370
Ensembl biotype	protein_coding
OMIM	605022
Entrez	5062

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 retained_intron

ENST00000327134, ENST00000426668, ENST00000481344, ENST00000871388, ENST00000871389, ENST00000871390, ENST00000871391, ENST00000915911, ENST00000915912, ENST00000959935, ENST00000959936, ENST00000959937

RefSeq mRNA: 1 — MANE Select: NM_002577 NM_002577

CCDS: CCDS3321

Canonical transcript exons

ENST00000327134 — 15 exons

Exon	Start	End
ENSE00001249990	196812739	196812851
ENSE00001249996	196812219	196812267
ENSE00001250037	196801927	196802027
ENSE00001250055	196828319	196832647
ENSE00001250062	196782626	196782833
ENSE00001350041	196739857	196740157
ENSE00001609930	196820371	196820567
ENSE00001771194	196810590	196810653
ENSE00002473911	196818057	196818156
ENSE00002482841	196827196	196827333
ENSE00002525797	196814451	196814568
ENSE00003486903	196803017	196803164
ENSE00003489843	196807782	196807914
ENSE00003532640	196806579	196806686
ENSE00003575973	196805352	196805383

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 97.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.6768 / max 797.7603, expressed in 1825 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
40745	64.8021	1824
40746	7.3477	1714
40747	1.3592	854
40752	1.1391	615
40749	0.3105	129
40748	0.3096	131
40751	0.2409	55
40744	0.1678	55

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ganglionic eminence	UBERON:0004023	97.23	gold quality
cortical plate	UBERON:0005343	96.37	gold quality
corpus callosum	UBERON:0002336	96.35	gold quality
ventricular zone	UBERON:0003053	95.97	gold quality
monocyte	CL:0000576	95.94	gold quality
mononuclear cell	CL:0000842	95.93	gold quality
leukocyte	CL:0000738	95.83	gold quality
superficial temporal artery	UBERON:0001614	95.60	gold quality
choroid plexus epithelium	UBERON:0003911	95.28	gold quality
stromal cell of endometrium	CL:0002255	94.74	gold quality
calcaneal tendon	UBERON:0003701	94.69	gold quality
pericardium	UBERON:0002407	94.64	gold quality
buccal mucosa cell	CL:0002336	94.52	gold quality
medial globus pallidus	UBERON:0002477	94.51	gold quality
synovial joint	UBERON:0002217	94.41	gold quality
saphenous vein	UBERON:0007318	94.36	gold quality
embryo	UBERON:0000922	94.31	gold quality
palpebral conjunctiva	UBERON:0001812	94.31	gold quality
tendon	UBERON:0000043	94.18	gold quality
urethra	UBERON:0000057	93.82	gold quality
globus pallidus	UBERON:0001875	93.63	gold quality
tibia	UBERON:0000979	93.62	gold quality
tendon of biceps brachii	UBERON:0008188	93.61	gold quality
blood	UBERON:0000178	93.55	gold quality
bone marrow cell	CL:0002092	93.52	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.52	gold quality
epithelium of nasopharynx	UBERON:0001951	93.50	gold quality
inferior vagus X ganglion	UBERON:0005363	93.42	gold quality
lymph node	UBERON:0000029	93.36	gold quality
cauda epididymis	UBERON:0004360	93.36	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.99
E-GEOD-110499	no	1435.14

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

297 targeting PAK2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 1 (little evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 12.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Cdc42/Rac1-dependent activation of PAK may trigger early platelet shape change, at least in part through the regulation of cortactin binding to PAK. (PMID:12453877)
• The enzymatic phosphorylation reaction of PAK2 can be best interpreted by a rapid-equilibrium random bi-bi reaction model; the catalysis reaction is partially limited by both the phosphoryl group transfer and the product release steps. (PMID:12549935)
• The opposing effects of Core protein on the transcription pf P21 might be important in the progression of liver disease in HCV-positive patients. (PMID:12823590)
• Caspase-activated PAK-2 is regulated by subcellular targeting and proteasomal degradation (PMID:12853446)
• sites of PAK2 autophosphorylation in the regulatory and the catalytic domains and their kinetic effect; multiple regions of PAK2 are involved in the enzyme-substrate recognition (PMID:12907671)
• Pak2 phosphorylates Myc at three sites (T358, S373, and T400) and affects Myc functions both in vitro and in vivo (PMID:14749374)
• Nef induces signal transduction via the recruitment of a signaling machinery including Pak2 into lipid rafts, thereby mimicking a physiological cellular mechanism to initiate the TCR cascade. (PMID:15047825)
• PAK2 is constitutively activated in certain breast cancer cell lines and that this active PAK is mislocalized to atypical focal adhesions in the absence of high levels of activated Rho GTPases. (PMID:15047871)
• PAK2 kinase activity is increased in response to TCR stimulation; results suggest a novel role for PAK2 as a positive regulator of T cell activation. (PMID:15187108)
• interacts with Nef proteins from SIV infected chimpanzees (PMID:15194762)
• Pak2 has a role in the down-regulation of translation initiation in apoptosis by phosphorylation of Mnk1 (PMID:15234964)
• PS-GAP is a novel regulator of caspase-activated PAK-2 (PMID:15471851)
• PAK-2 is activated in 1-LN prostate cancer cells by a proteinase inhibitor, alpha 2-macroglobulin (PMID:15908432)
• binding of Cdc42 localizes Pak2 to the endoplasmic reticulum, where autophosphorylation alters association of the two proteins (PMID:16204230)
• Pak2 binds to and phosphorylates initiation factor eIF4G, which inhibits association of eIF4E with m7GTP, reducing translation initiation. (PMID:16281055)
• Nef protein amino acids at positions 85, 89, 187, 188, and 191 (L, H, S, R, and F in the clade B consensus, respectively) are critical for Pak2 association and activation (PMID:16501114)
• Posttranslational myristoylation of PAK2 might be part of a unique series of mechanisms involved in the regulation of the later events of apoptosis. (PMID:16617111)
• c-Abl represents a target downstream of phosphatidylinositol 3-kinase-activated PAK2, which differentiates TGF-beta signaling in fibroblasts and epithelial cell lines. (PMID:16867995)
• This study of tissue-derived HIV-1 Nefs demonstrates that CD4 and MHC-I downregulation are highly conserved Nef functions, while Pak2 association is variable in late stage AIDS patients. (PMID:16979207)
• define a new class of PAK-interacting proteins, which play an important role in actin cytoskeletal reorganization (PMID:17543336)
• bring novel insights into our understanding of synergistic regulation of MUC5AC mucin by both pathological and physiological inducers (PMID:17555715)
• interaction of Nef with PAK2 does not play a major role in T-cell activation, viral replication, and apoptosis. (PMID:17881449)
• protein phosphatase 1alpha can act directly on phosphorylated Thr-402 in the activation loop of PAK2 and down-regulate its kinase activity (PMID:18176785)
• Data show RNAi-mediated or dominant-negative suppression of Pak2, major regulators of cytoskeletal signaling downstream of Cdc42 or Rac1, markedly inhibits EC lumen and tube formation. (PMID:18319301)
• Clathrin-independent endocytosis used by the IL-2 receptor is regulated by Rac1, Pak1 and Pak2. (PMID:18344974)
• Pak1 and Pak2 mediate tumor cell invasion through distinct signaling mechanisms (PMID:18411304)
• Huntingtin exerts anti-apoptotic effects by binding to Pak2, which reduces the abilities of caspase-3 and caspase-8 to cleave Pak2 and convert it into a mediator of cell death. (PMID:19240112)
• PAK-2 activity controls the apoptotic response by regulating levels of activated caspase 3 and thereby its own cleavage to the proapoptotic PAK-2p34 fragment (PMID:19242610)
• Knockdown of PAK2 enhances loss of cell-cell junctions and increases lamellipodium extension but does not affect migration speed Hepatocyte Growth Factor (HGF) stimulated DU145 prostate carcinoma cells. (PMID:19628037)
• MYO18A is a novel binding partner of the PAK2/betaPIX/GIT1 complex and suggest that MYO18A may play an important role in regulating epithelial cell migration via affecting multiple cell machineries. (PMID:19923322)
• Our studies suggest that Rac1 –> Pak1/Pak2 –> NFkappaB is a separate pathway that contributes to the expression of COX-2 in HPV-induced papillomas, independently of the previously described Rac1 –> p38 –> COX-2 pathway. (PMID:20131316)
• analysis of evolutionary conserved residues that are crucial for the catalytic activity of PKA and Pak2 (PMID:20209159)
• Rac1/Cdc42/PAK pathway controls actin reorganization that is necessary for microvesicle shedding (PMID:20523167)
• The association between the CD4 receptor and protein kinase pp58 and the protein-tyrosine kinase within the cell introduces a specific pathway by which T lymphocytes become activated. (PMID:20724730)
• Mechanistic studies of the autoactivation of PAK2: a two-step model of cis initiation followed by trans amplification. (PMID:21098037)
• High PAK2 is associated with melanoma. (PMID:21177766)
• highly expressed PAK2 mediates chemotherapeutic resistance in human breast invasive ductal carcinoma by negatively regulating caspase-7 activity (PMID:21555521)
• The ability of Nef to associate with PAK2 correlates with the ability to enhance HIV-1 replication. (PMID:21819585)
• Low-to-moderate penetrance protein coding mutations or non-coding mutations at DLG1 and/or PAK2, or a nearby gene, may reproduce the behavioral characteristics of the 3q29 microdeletion. (PMID:21850710)
• PAK2 negatively modulate TGF-beta signaling by attenuating the receptor-Smad interaction and thus Smad activation (PMID:22393057)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pak2b	ENSDARG00000018476
danio_rerio	pak2a	ENSDARG00000068177
mus_musculus	Pak2	ENSMUSG00000022781
rattus_norvegicus	Pak2	ENSRNOG00000001747
drosophila_melanogaster	Pak	FBGN0267698

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), PAK5 (ENSG00000101349), STK24 (ENSG00000102572), STK3 (ENSG00000104375), MAP4K1 (ENSG00000104814), MAP3K8 (ENSG00000107968), MAP2K6 (ENSG00000108984), NEK4 (ENSG00000114904), STK25 (ENSG00000115694), NRK (ENSG00000123572), PAK4 (ENSG00000130669), STK26 (ENSG00000134602), TAOK3 (ENSG00000135090), PAK6 (ENSG00000137843), MINK1 (ENSG00000141503), PAK1 (ENSG00000149269), TAOK2 (ENSG00000149930), TNIK (ENSG00000154310), TAOK1 (ENSG00000160551), MAP4K2 (ENSG00000168067), OXSR1 (ENSG00000172939), MAP3K19 (ENSG00000176601), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Serine/threonine-protein kinase PAK 2 — Q13177 (reviewed: Q13177)

Alternative names: Gamma-PAK, PAK65, S6/H4 kinase, p21-activated kinase 2, p58

All UniProt accessions (2): Q13177, H7C1X3

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation. Acts as a downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Full-length PAK2 stimulates cell survival and cell growth. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Phosphorylates JUN and plays an important role in EGF-induced cell proliferation. Phosphorylates many other substrates including histone H4 to promote assembly of H3.3 and H4 into nucleosomes, BAD, ribosomal protein S6, or MBP. Phosphorylates CASP7, thereby preventing its activity. Additionally, associates with ARHGEF7 and GIT1 to perform kinase-independent functions such as spindle orientation control during mitosis. On the other hand, apoptotic stimuli such as DNA damage lead to caspase-mediated cleavage of PAK2, generating PAK-2p34, an active p34 fragment that translocates to the nucleus and promotes cellular apoptosis involving the JNK signaling pathway. Caspase-activated PAK2 phosphorylates MKNK1 and reduces cellular translation.

Subunit / interactions. Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Interacts with SH3MD4. Interacts with SCRIB. Interacts with ARHGEF7 and GIT1. PAK-2p34 interacts with ARHGAP10. (Microbial infection) Interacts with and activated by HIV-1 Nef.

Subcellular location. Cytoplasm. Nucleus Nucleus. Perinuclear region. Membrane.

Tissue specificity. Ubiquitously expressed. Higher levels seen in skeletal muscle, ovary, thymus and spleen.

Post-translational modifications. Full-length PAK2 is autophosphorylated when activated by CDC42/p21. Following cleavage, both peptides, PAK-2p27 and PAK-2p34, become highly autophosphorylated, with PAK-2p27 being phosphorylated on serine and PAK-2p34 on threonine residues, respectively. Autophosphorylation of PAK-2p27 can occur in the absence of any effectors and is dependent on phosphorylation of Thr-402, because PAK-2p27 is acting as an exogenous substrate. During apoptosis proteolytically cleaved by caspase-3 or caspase-3-like proteases to yield active PAK-2p34. Ubiquitinated, leading to its proteasomal degradation. PAK-2p34 is myristoylated.

Disease relevance. Knobloch syndrome 2 (KNO2) [MIM:618458] An autosomal dominant form of Knobloch syndrome characterized by high myopia, vitreoretinal degeneration, retinal detachment, occipital encephalocele or scalp lesions, and mild to severe psychomotor delay. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by binding small G proteins. Binding of GTP-bound CDC42 or RAC1 to the autoregulatory region releases monomers from the autoinhibited dimer, enables phosphorylation of Thr-402 and allows the kinase domain to adopt an active structure. Following caspase cleavage, autophosphorylated PAK-2p34 is constitutively active.

Similarity. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily.

RefSeq proteins (1): NP_002568* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000095	CRIB_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR033923	PAK_BD	Domain
IPR035064	STK_PAK2	Domain
IPR036936	CRIB_dom_sf	Homologous_superfamily
IPR051931	PAK3-like	Family

Pfam: PF00069, PF00786

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (51 total): modified residue 18, mutagenesis site 6, sequence conflict 6, region of interest 5, chain 3, compositionally biased region 2, binding site 2, domain 2, initiator methionine 1, short sequence motif 1, active site 1, site 1, lipid moiety-binding region 1, sequence variant 1, helix 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9D51	X-RAY DIFFRACTION	2.1
9LBF	X-RAY DIFFRACTION	2.62
3PCS	X-RAY DIFFRACTION	2.86
9LBG	X-RAY DIFFRACTION	2.89
9M41	X-RAY DIFFRACTION	3.02

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13177-F1	75.06	0.45

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (2): 367 (proton acceptor); 212–213 (cleavage; by caspase-3 or caspase-3-like proteases)

Ligand- & substrate-binding residues (2): 255–263; 278

Post-translational modifications (19): 2, 2, 20, 55, 58, 60, 62, 64, 128, 134, 139, 141, 143, 152, 154, 169, 197, 402, 213

Mutagenesis-validated functional residues (6):

Position	Phenotype
212	inhibits caspase-mediated cleavage.
213	abolishes myristoylation of pak-2p34 and membrane location.
239–243	abolishes nuclear export.
246–248	greatly inhibits nuclear localization.
278	abolishes kinase activity and autophosphorylation.
402	abolishes kinase activity and greatly inhibits autophosphorylation of pak-2p27 and pak-2p34.

Function

Pathways and Gene Ontology

Reactome pathways

27 pathways

ID	Pathway
R-HSA-164944	Nef and signal transduction
R-HSA-202433	Generation of second messenger molecules
R-HSA-211728	Regulation of PAK-2p34 activity by PS-GAP/RHG10
R-HSA-211733	Regulation of activated PAK-2p34 by proteasome mediated degradation
R-HSA-211736	Stimulation of the cell death response by PAK-2p34
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-389359	CD28 dependent Vav1 pathway
R-HSA-3928664	Ephrin signaling
R-HSA-399954	Sema3A PAK dependent Axon repulsion
R-HSA-428540	Activation of RAC1
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-445355	Smooth Muscle Contraction
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-5621575	CD209 (DC-SIGN) signaling
R-HSA-5627123	RHO GTPases activate PAKs
R-HSA-5687128	MAPK6/MAPK4 signaling
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013407	RHOH GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9013420	RHOU GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-9013424	RHOV GTPase cycle

MSigDB gene sets: 552 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_DENDRITE_DEVELOPMENT, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, WANG_CLIM2_TARGETS_UP, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GNF2_BNIP2, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_APICAL_JUNCTION_ASSEMBLY

GO Biological Process (27): stimulatory C-type lectin receptor signaling pathway (GO:0002223), cardiac muscle hypertrophy (GO:0003300), protein phosphorylation (GO:0006468), negative regulation of protein kinase activity (GO:0006469), apoptotic process (GO:0006915), signal transduction (GO:0007165), cellular response to starvation (GO:0009267), cell migration (GO:0016477), adherens junction assembly (GO:0034333), intracellular signal transduction (GO:0035556), negative regulation of apoptotic process (GO:0043066), regulation of MAPK cascade (GO:0043408), protein autophosphorylation (GO:0046777), vascular endothelial growth factor receptor signaling pathway (GO:0048010), regulation of axonogenesis (GO:0050770), regulation of cytoskeleton organization (GO:0051493), negative regulation of stress fiber assembly (GO:0051497), dendritic spine development (GO:0060996), bicellular tight junction assembly (GO:0070830), cellular response to transforming growth factor beta stimulus (GO:0071560), protein localization to cell-cell junction (GO:0150105), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), protein maturation (GO:0051604), execution phase of apoptosis (GO:0097194), regulation of actin filament organization (GO:0110053), positive regulation of execution phase of apoptosis (GO:1900119)

GO Molecular Function (15): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein kinase binding (GO:0019901), protein tyrosine kinase activator activity (GO:0030296), small GTPase binding (GO:0031267), identical protein binding (GO:0042802), cadherin binding (GO:0045296), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (13): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), postsynaptic density (GO:0014069), nuclear speck (GO:0016607), secretory granule (GO:0030141), perinuclear region of cytoplasm (GO:0048471), glutamatergic synapse (GO:0098978), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
RHO GTPase cycle	3
Regulation of Apoptosis	2
The role of Nef in HIV-1 replication and disease pathogenesis	1
TCR signaling	1
Apoptotic execution phase	1
Fc epsilon receptor (FCERI) signaling	1
Co-stimulation by CD28	1
EPH-Ephrin signaling	1
Semaphorin interactions	1
Signaling by ROBO receptors	1
Signaling by VEGF	1
Muscle contraction	1
VEGFA-VEGFR2 Pathway	1
C-type lectin receptors (CLRs)	1
RHO GTPase Effectors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein kinase activity	3
intracellular anatomical structure	2
cytoplasm	2
innate immune response activating cell surface receptor signaling pathway	1
cellular response to lectin	1
striated muscle hypertrophy	1
phosphorylation	1
protein modification process	1
negative regulation of protein phosphorylation	1
negative regulation of kinase activity	1
regulation of protein kinase activity	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
cell motility	1
cell-cell junction assembly	1
adherens junction organization	1
signal transduction	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
MAPK cascade	1
regulation of intracellular signal transduction	1
protein phosphorylation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
axonogenesis	1
regulation of neuron projection development	1
regulation of anatomical structure morphogenesis	1
cytoskeleton organization	1
regulation of organelle organization	1
negative regulation of actin filament bundle assembly	1

Protein interactions and networks

STRING

2646 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAK2	ARHGAP10	A1A4S6	853
PAK2	CDC42	P21181	849
PAK2	RAC2	P15153	692
PAK2	RAC1	P15154	666
PAK2	RHOA	P06749	592
PAK2	MPP3	Q13368	548
PAK2	DLG3	Q92796	546
PAK2	RHOC	P08134	516
PAK2	VAV1	P15498	514
PAK2	CCNB1	P14635	506
PAK2	AKT1	P31749	499
PAK2	ARHGEF7	Q14155	489
PAK2	ARPC3	O15145	464
PAK2	DCTN5	Q9BTE1	462
PAK2	MAPK1	P28482	448

IntAct

259 interactions, top by confidence:

A	B	Type	Score
ARHGEF7	PAK1	psi-mi:“MI:0914”(association)	0.950
PAK2	CDC42	psi-mi:“MI:0915”(physical association)	0.870
CDC42	PAK2	psi-mi:“MI:0915”(physical association)	0.870
NCK2	PAK2	psi-mi:“MI:0915”(physical association)	0.840
PAK2	NCK2	psi-mi:“MI:0914”(association)	0.840
PAK2	NCK1	psi-mi:“MI:0915”(physical association)	0.830
PAK2	ARHGEF6	psi-mi:“MI:0915”(physical association)	0.830
NCK1	PAK2	psi-mi:“MI:0915”(physical association)	0.830
	RAB8A	psi-mi:“MI:0217”(phosphorylation reaction)	0.820
ARHGEF6	PAK1	psi-mi:“MI:0914”(association)	0.800
	RAB8A	psi-mi:“MI:0217”(phosphorylation reaction)	0.790
RHOJ	PAK2	psi-mi:“MI:0915”(physical association)	0.780
PAK2	RHOJ	psi-mi:“MI:0915”(physical association)	0.780
NAPA	SNAP23	psi-mi:“MI:0914”(association)	0.780
PAK2	SORBS3	psi-mi:“MI:0915”(physical association)	0.770
NHERF2	PODXL	psi-mi:“MI:0914”(association)	0.770
FBXO28	TRAF5	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TAX1BP3	ARVCF	psi-mi:“MI:0914”(association)	0.690

BioGRID (290): PAK2 (Two-hybrid), SORBS3 (Two-hybrid), RHOJ (Two-hybrid), PAK2 (Affinity Capture-MS), PAK2 (Affinity Capture-MS), PAK2 (Affinity Capture-MS), PAK2 (Affinity Capture-MS), PAK2 (Affinity Capture-MS), PAK2 (Affinity Capture-MS), GDI1 (Co-fractionation), MYO6 (Co-fractionation), PAK2 (Co-fractionation), PAK2 (Co-fractionation), PAK2 (Co-fractionation), PAK2 (Co-fractionation)

ESM2 similar proteins: A0A087WV53, A1CS92, A2ABU4, A2Q908, A2RUH7, A4QZL9, D3ZHA0, O01761, O70468, O75369, O88599, P05548, P11275, P11730, P11798, P13466, P21333, P56276, P56741, P70402, P79280, Q05623, Q13177, Q13203, Q13557, Q14315, Q2GM53, Q2HJF7, Q2URB7, Q5FW53, Q5PQM4, Q5RCC4, Q5VTT5, Q5ZJJ9, Q5ZKI0, Q62422, Q63518, Q6C1H8, Q6P686, Q6PHZ2

Diamond homologs: A0A7J6K7I9, A0A7J6K7Y0, A0A7J6KD88, A8X775, B1WAR9, C4YRB7, D2HXI8, E1C2I2, E9PSL7, G1X456, G5EGQ3, M3TYT0, O00506, O01583, O01700, O14578, O54874, O61267, O75116, O77819, O80902, O88643, O97627, P05131, P0CY23, P0CY24, P13677, P21146, P25098, P26817, P26818, P32865, P34100, P35465, P38070, P48562, P49025, P49673, P54265, P70335

SIGNOR signaling

50 interactions.

A	Effect	B	Mechanism
PAK2	up-regulates	PAK2	phosphorylation
PAK2	down-regulates	NF2	phosphorylation
PAK2	down-regulates	ABL1	phosphorylation
PPM1F	down-regulates	PAK2	dephosphorylation
PAK2	up-regulates	JUN	phosphorylation
PAK2	down-regulates	CASP7	phosphorylation
PAK2	up-regulates	PRL	phosphorylation
PRKAA2	unknown	PAK2	phosphorylation
AMPK	unknown	PAK2	phosphorylation
PAK2	“down-regulates activity”	MKNK1	phosphorylation
CDK12	“up-regulates activity”	PAK2	phosphorylation
CyclinK/CDK12	“up-regulates activity”	PAK2	phosphorylation
PAK2	“down-regulates activity”	SORT1	phosphorylation
PAK2	“down-regulates activity”	PREX2	phosphorylation
hsa-miR-23b-3p	“down-regulates quantity by repression”	PAK2	“post transcriptional regulation”
PAK2	“down-regulates activity”	MYC	phosphorylation
PAK2	“up-regulates activity”	SYK	phosphorylation
SRC	up-regulates	PAK2	phosphorylation
RAC1	“up-regulates activity”	PAK2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 161 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RHO GTPases activate PAKs	6	26.5×	1e-05
Ephrin signaling	5	23.2×	1e-04
RHOU GTPase cycle	10	22.6×	1e-08
RHOV GTPase cycle	8	18.6×	2e-06
RHO GTPases activate PKNs	6	15.5×	2e-04
RHOJ GTPase cycle	9	14.7×	2e-06
Late endosomal microautophagy	5	13.3×	1e-03
Signaling by high-kinase activity BRAF mutants	5	12.9×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of substrate adhesion-dependent cell spreading	7	18.2×	4e-05
positive regulation of axon extension	5	17.7×	2e-03
negative regulation of protein-containing complex assembly	5	15.8×	3e-03
lamellipodium assembly	5	15.4×	3e-03
positive regulation of stress fiber assembly	7	15.2×	1e-04
ephrin receptor signaling pathway	5	11.9×	7e-03
mitotic spindle organization	6	11.3×	3e-03
positive regulation of neuron projection development	7	6.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

82 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	52
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1697333	NM_002577.4(PAK2):c.1303G>A (p.Glu435Lys)	Pathogenic
2921281	NM_002577.4(PAK2):c.1273G>A (p.Asp425Asn)	Likely pathogenic
3362907	NM_002577.4(PAK2):c.836A>C (p.Gln279Pro)	Likely pathogenic

SpliceAI

2887 predictions. Top by Δscore:

Variant	Effect	Δscore
3:196782621:TCCA:T	acceptor_loss	1.0000
3:196782623:CA:C	acceptor_loss	1.0000
3:196782624:A:AC	acceptor_loss	1.0000
3:196782624:A:AG	acceptor_gain	1.0000
3:196782624:AG:A	acceptor_gain	1.0000
3:196782625:G:GT	acceptor_gain	1.0000
3:196782625:GG:G	acceptor_gain	1.0000
3:196782625:GGC:G	acceptor_gain	1.0000
3:196782625:GGCC:G	acceptor_gain	1.0000
3:196782625:GGCCA:G	acceptor_gain	1.0000
3:196782829:GAAAG:G	donor_gain	1.0000
3:196782830:AAAGG:A	donor_loss	1.0000
3:196782831:AAG:A	donor_loss	1.0000
3:196782832:AGG:A	donor_loss	1.0000
3:196782833:GG:G	donor_loss	1.0000
3:196782834:GTAA:G	donor_loss	1.0000
3:196782835:T:C	donor_loss	1.0000
3:196801915:A:AG	acceptor_gain	1.0000
3:196801915:AAT:A	acceptor_gain	1.0000
3:196801916:A:G	acceptor_gain	1.0000
3:196801917:T:G	acceptor_gain	1.0000
3:196801917:T:TA	acceptor_gain	1.0000
3:196801924:TAG:T	acceptor_loss	1.0000
3:196801925:A:AG	acceptor_gain	1.0000
3:196801925:A:G	acceptor_loss	1.0000
3:196801925:AG:A	acceptor_gain	1.0000
3:196801926:G:GA	acceptor_gain	1.0000
3:196801926:GG:G	acceptor_gain	1.0000
3:196801926:GGA:G	acceptor_gain	1.0000
3:196801926:GGAA:G	acceptor_gain	1.0000

AlphaMissense

3447 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:196801960:T:A	I74N	1.000
3:196801960:T:C	I74T	1.000
3:196801960:T:G	I74S	1.000
3:196801969:C:A	P77Q	1.000
3:196801977:T:C	F80L	1.000
3:196801979:T:A	F80L	1.000
3:196801979:T:G	F80L	1.000
3:196801983:C:G	H82D	1.000
3:196801992:C:A	H85N	1.000
3:196801992:C:G	H85D	1.000
3:196801994:T:A	H85Q	1.000
3:196801994:T:G	H85Q	1.000
3:196801996:T:A	V86D	1.000
3:196802022:T:C	F95L	1.000
3:196802023:T:C	F95S	1.000
3:196802023:T:G	F95C	1.000
3:196802024:C:A	F95L	1.000
3:196802024:C:G	F95L	1.000
3:196803017:G:C	G97R	1.000
3:196803032:T:A	W102R	1.000
3:196803032:T:C	W102R	1.000
3:196803034:G:C	W102C	1.000
3:196803034:G:T	W102C	1.000
3:196803045:T:C	L106P	1.000
3:196803053:T:C	S109P	1.000
3:196803060:T:A	I111N	1.000
3:196803060:T:C	I111T	1.000
3:196803060:T:G	I111S	1.000
3:196803075:A:C	Q116P	1.000
3:196803096:T:A	V123E	1.000

dbSNP variants (sampled 300 via entrez): RS1000006892 (3:196750004 G>T), RS1000065325 (3:196754925 G>A), RS1000109617 (3:196746561 C>T), RS1000118324 (3:196740188 C>T), RS1000208072 (3:196764710 C>T), RS1000302711 (3:196765342 G>T), RS1000318634 (3:196822259 T>C), RS1000321470 (3:196802370 C>T), RS1000345293 (3:196811725 T>C), RS1000378230 (3:196811995 ATTT>A), RS1000388765 (3:196757113 G>A,C,T), RS1000401799 (3:196773749 C>A,T), RS1000402513 (3:196751579 G>A), RS1000510996 (3:196794801 TC>T), RS1000517119 (3:196800631 G>T)

Disease associations

OMIM: gene MIM:605022 | disease phenotypes: MIM:267750, MIM:618458

GenCC curated gene-disease

Disease	Classification	Inheritance
Knobloch syndrome 2	Strong	Autosomal dominant

Mondo (2): Knobloch syndrome (MONDO:0800166), Knobloch syndrome 2 (MONDO:0100119)

Orphanet (1): Knobloch syndrome (Orphanet:1571)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000076	Vesicoureteral reflux
HP:0000238	Hydrocephalus
HP:0000286	Epicanthus
HP:0000347	Micrognathia
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000529	Progressive visual loss
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000572	Visual loss
HP:0000608	Macular degeneration
HP:0000639	Nystagmus
HP:0000717	Autism
HP:0001083	Ectopia lentis
HP:0001195	Single umbilical artery
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001362	Calvarial skull defect
HP:0001382	Joint hypermobility
HP:0001595	Abnormal hair morphology
HP:0001643	Patent ductus arteriosus
HP:0001651	Dextrocardia
HP:0002021	Pyloric stenosis
HP:0002084	Encephalocele
HP:0002085	Occipital encephalocele
HP:0002205	Recurrent respiratory infections
HP:0004327	Abnormal vitreous humor morphology
HP:0005280	Depressed nasal bridge

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST000892_3	Total ventricular volume (Alzheimer’s disease interaction)	5.000000e-06
GCST002726_27	Glucose homeostasis traits	9.000000e-06
GCST004603_264	Platelet count	4.000000e-11
GCST004606_108	Eosinophil count	2.000000e-09
GCST004607_269	Plateletcrit	3.000000e-18
GCST004610_63	White blood cell count	9.000000e-17
GCST004624_40	Sum eosinophil basophil counts	1.000000e-10
GCST004625_78	Monocyte count	2.000000e-10
GCST004627_52	Lymphocyte count	3.000000e-22
GCST006061_101	Atrial fibrillation	2.000000e-08
GCST009798_34	Asthma	4.000000e-12
GCST010725_2	Malaria	8.000000e-06
GCST90002381_201	Eosinophil count	1.000000e-15
GCST90002388_208	Lymphocyte count	2.000000e-56
GCST90002391_19	Mean corpuscular hemoglobin concentration	3.000000e-18
GCST90002393_215	Monocyte count	2.000000e-39
GCST90002397_98	Mean spheric corpuscular volume	1.000000e-29
GCST90002398_440	Neutrophil count	2.000000e-22
GCST90002400_421	Plateletcrit	1.000000e-42
GCST90002401_141	Platelet distribution width	3.000000e-12
GCST90002402_673	Platelet count	5.000000e-23
GCST90002404_76	Red cell distribution width	4.000000e-11
GCST90002406_82	Reticulocyte fraction of red cells	6.000000e-09
GCST90002407_420	White blood cell count	3.000000e-55

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004471	insulin sensitivity measurement
EFO:0004309	platelet count
EFO:0004842	eosinophil count
EFO:0007985	platelet crit
EFO:0005090	basophil count
EFO:0005091	monocyte count
EFO:0004587	lymphocyte count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004833	neutrophil count
EFO:0007984	platelet component distribution width
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL3885636 (PROTEIN FAMILY), CHEMBL3885637 (PROTEIN FAMILY), CHEMBL4487 (SINGLE PROTEIN), CHEMBL5291683 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 47,693 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL180022	NERATINIB	4	9,404
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL603469	LESTAURTINIB	3
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL1908397	KW-2449	1	622
CHEMBL3128043	PF-03758309	1	233
CHEMBL494089	GSK-690693	1	2,061

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — PAKA subfamily

Most potent curated ligand interactions (8 total), top 8:

Ligand	Action	Affinity	Parameter
staurosporine	Inhibition	9.0	pIC50
PQA-18	Inhibition	8.0	pIC50
FRAX597	Inhibition	7.89	pIC50
FRAX486	Inhibition	7.4	pIC50
Il-94	Inhibition	7.19	pIC50
PF-3758309	Inhibition	6.72	pIC50
compound 3 [PMID: 26191365]	Negative	6.4	pKd
compound 4 [PMID: 24432870]	Inhibition	6.01	pIC50

Binding affinities (BindingDB)

4 measured of 5 human assays (5 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
FRAX597	IC50	7.7 nM
PKC-412	KD	190 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM

ChEMBL bioactivities

93 potent at pChembl≥5 of 100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.49	Kd	0.32	nM	CHEMBL3923175
9.00	IC50	1	nM	STAUROSPORINE
8.93	IC50	1.17	nM	STAUROSPORINE
8.70	Ki	2	nM	CHEMBL3818265
8.59	IC50	2.59	nM	STAUROSPORINE
8.57	IC50	2.67	nM	STAUROSPORINE
8.51	Kd	3.1	nM	STAUROSPORINE
8.46	IC50	3.46	nM	STAUROSPORINE
8.40	Kd	4	nM	KW-2449
8.34	Ki	4.6	nM	CHEMBL3818479
8.22	IC50	6	nM	CHEMBL3923175
8.02	Ki	9.5	nM	CHEMBL3819118
8.00	IC50	10	nM	CHEMBL3609326
7.96	IC50	11	nM	CHEMBL3770443
7.96	Ki	11	nM	CHEMBL3770443
7.89	IC50	12.8	nM	CHEMBL3609327
7.89	IC50	12.8	nM	CHEMBL5661936
7.72	IC50	19	nM	CHEMBL3609327
7.68	Ki	21	nM	CHEMBL3817984
7.48	IC50	33	nM	CHEMBL3818265
7.41	Ki	39	nM	CHEMBL3819447
7.40	IC50	39.5	nM	CHEMBL3609326
7.39	IC50	41	nM	CHEMBL5090394
7.37	Kd	43	nM	LESTAURTINIB
7.32	Ki	48	nM	CHEMBL3770186
7.29	IC50	51	nM	CHEMBL3824314
7.24	IC50	57	nM	CHEMBL3824224
7.19	IC50	64.1	nM	CHEMBL2386715
7.17	IC50	68	nM	CHEMBL3823612
7.15	IC50	70.8	nM	CHEMBL2386717
7.15	IC50	71	nM	CHEMBL3770443
7.14	IC50	72	nM	CHEMBL3824061
7.11	IC50	78	nM	CHEMBL3817856
7.10	Kd	79	nM	NERATINIB
7.06	IC50	88	nM	CHEMBL3818828
7.04	IC50	92	nM	CHEMBL3823614
6.92	IC50	120	nM	CHEMBL3580968
6.88	IC50	133	nM	CHEMBL2386716
6.82	IC50	150	nM	CHEMBL3817984
6.80	IC50	160	nM	CHEMBL3823523
6.75	IC50	180	nM	CHEMBL3824243
6.72	IC50	190	nM	PF-03758309
6.72	IC50	190	nM	CHEMBL3823258
6.71	IC50	192.7	nM	CHEMBL5619359
6.66	IC50	220	nM	CHEMBL3770186
6.62	IC50	240	nM	CHEMBL3819118
6.62	IC50	240	nM	CHEMBL3823457
6.61	IC50	244	nM	CHEMBL2386718
6.60	IC50	250	nM	CHEMBL3822836
6.57	IC50	270	nM	CHEMBL3823056

PubChem BioAssay actives

90 with measured affinity, of 1152 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[[N-[2-[3-ethylsulfonyl-4-(4-methylpiperazin-1-yl)anilino]-5-fluoropyrimidin-4-yl]-5-(hydroxymethyl)-2-methylanilino]methyl]benzonitrile	1326094: Binding affinity to human PAK2 (P151 to R525 residues) expressed in bacterial expression system by KINOMEscan assay	kd	0.0003	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	350548: Inhibition of PAK2	ic50	0.0010	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-[2-(3-fluoro-1-methylazetidin-3-yl)ethyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308782: Inhibition of human recombinant PAK2 assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0020	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	1425099: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0040	uM
6-[2-chloro-4-(3-methyl-2-oxopyrazin-1-yl)phenyl]-8-[(3,3-difluoropiperidin-4-yl)methyl]-2-(oxetan-3-ylamino)pyrido[2,3-d]pyrimidin-7-one	1308782: Inhibition of human recombinant PAK2 assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0046	uM
6-[2-chloro-4-(3-ethyl-2-oxo-1-pyridinyl)phenyl]-2-(methylamino)-8-[[(2R)-morpholin-2-yl]methyl]pyrido[2,3-d]pyrimidin-7-one	1308782: Inhibition of human recombinant PAK2 assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0095	uM
6-(2,4-dichlorophenyl)-8-ethyl-2-(3-fluoro-4-piperazin-1-ylanilino)pyrido[2,3-d]pyrimidin-7-one	2155038: Inhibition of full length PAK2 (unknown origin) assessed s reduction in substrate phosphorylation using peptide as substrate by FRET based Z-LYTE kinase assay	ic50	0.0100	uM
8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(6-methyl-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1280640: Inhibition of human recombinant PAK2	ic50	0.0110	uM
6-[2-chloro-4-(1,3-thiazol-5-yl)phenyl]-8-ethyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one	1242472: Inhibition of recombinant human PAK2 by Z’-LYTE assay	ic50	0.0128	uM
6-[2-chloro-4-(1,3-thiazol-5-yl)phenyl]-8-ethyl-2-[4-(4-methylpiperazin-1-yl)anilino]pyrido[2,3-d]pyrimidin-7-one;hydrochloride	2152562: Inhibition of PAK2 (unknown origin) by Z-LYTE biochemical assay	ic50	0.0128	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-ethyl-2-(oxetan-3-ylamino)pyrido[2,3-d]pyrimidin-7-one	1308782: Inhibition of human recombinant PAK2 assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0210	uM
6-[2-chloro-4-(5-methyl-6-oxopyrimidin-1-yl)phenyl]-8-(2-methoxyethyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308782: Inhibition of human recombinant PAK2 assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0390	uM
8-[(5-amino-1,3-dioxan-2-yl)methyl]-6-[2-chloro-4-(3-fluoro-2-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1895122: Inhibition of human PAK2 by radiometric PanQinase activity assay	ic50	0.0410	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	507657: Binding affinity to PAK2	kd	0.0430	uM
6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]-8-ethyl-2-[2-(1-methylpiperidin-4-yl)ethylamino]pyrido[2,3-d]pyrimidin-7-one	1308782: Inhibition of human recombinant PAK2 assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.0480	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0510	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(6-fluoro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0570	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(6-fluoro-1H-indazol-4-yl)methyl]-2-N-(2-methoxyethyl)pyrimidine-2,4-diamine	748653: Inhibition of PAK2-mediated MEK1 phosphorylation at Ser298 in human EBC1 cells after 2 hrs by HTRF assay	ic50	0.0641	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-pyrrolo[2,3-c]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0680	uM
2-[[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]-[(6-fluoro-1H-indazol-4-yl)methyl]amino]propan-1-ol	748653: Inhibition of PAK2-mediated MEK1 phosphorylation at Ser298 in human EBC1 cells after 2 hrs by HTRF assay	ic50	0.0708	uM
4-N-[5-[(1R,2S)-2-fluorocyclopropyl]-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0720	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-[(3,3-difluoropiperidin-4-yl)methyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308776: Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	ic50	0.0780	uM
Neratinib	624872: Binding constant for PAK2 kinase domain	kd	0.0790	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-2-(methylamino)-8-[2-(1-methylazetidin-3-yl)oxyethyl]pyrido[2,3-d]pyrimidin-7-one	1308776: Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	ic50	0.0880	uM
4-N-[5-[(1S,2R)-2-fluorocyclopropyl]-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.0920	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-indol-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.1200	uM
4-N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-indol-5-yl)ethyl]pyrimidine-2,4-diamine	748653: Inhibition of PAK2-mediated MEK1 phosphorylation at Ser298 in human EBC1 cells after 2 hrs by HTRF assay	ic50	0.1330	uM
2-N-[(1S)-1-(3-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]-4-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.1600	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)propyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.1800	uM
2-N-[(1S)-1-(6-chloro-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]-4-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.1900	uM
N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methylthieno[3,2-d]pyrimidin-4-yl)amino]-1,4-dihydropyrrolo[3,4-d]pyrazole-5-carboxamide	1242466: Inhibition of PAK2 (unknown origin)	ic50	0.1900	uM
6-[2-(cyclopropylamino)-6-(2,4-dichlorophenyl)-7-oxopyrido[2,3-d]pyrimidin-8-yl]-N-hydroxyhexanamide	2128136: Inhibition of PAK2 (unknown origin)	ic50	0.1927	uM
4-N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-N-methyl-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.2400	uM
2-N-[(1S)-1-(3H-benzimidazol-5-yl)ethyl]-4-N-[5-(2,2-difluorocyclopropyl)-1H-pyrazol-3-yl]pyrimidine-2,4-diamine	748653: Inhibition of PAK2-mediated MEK1 phosphorylation at Ser298 in human EBC1 cells after 2 hrs by HTRF assay	ic50	0.2440	uM
4-N-[5-(3,3-difluorocyclobutyl)-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.2500	uM
4-[2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-[[(3S)-piperidin-3-yl]methoxy]imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol	624872: Binding constant for PAK2 kinase domain	kd	0.2700	uM
4-N-[5-[(1S,2S)-2-fluorocyclopropyl]-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.2700	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-(2-methoxyethyl)-2-(oxetan-3-ylamino)pyrido[2,3-d]pyrimidin-7-one	1308776: Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	ic50	0.2900	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624872: Binding constant for PAK2 kinase domain	kd	0.3400	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-ethyl-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308776: Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	ic50	0.3400	uM
(3S)-3-[[8-chloro-11-(2,2-difluoroethyl)-3-fluoro-5H-benzo[b][1,4]benzodiazepin-6-ylidene]amino]-N-propan-2-ylpyrrolidine-1-carboxamide	1242441: Binding affinity to PAK2 (unknown origin) expressed in HEK293 cells after 1 hr by qPCR analysis	kd	0.4000	uM
3-[[8-chloro-11-(2,2-difluoroethyl)-3-fluoro-5H-benzo[b][1,4]benzodiazepin-6-ylidene]amino]-N-propan-2-ylpyrrolidine-1-carboxamide	2171532: Binding affinity to PAK2 (unknown origin) assessed as dissociation constant	kd	0.4000	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-(2-methoxyethyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308776: Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	ic50	0.4500	uM
8-(3-amino-2,2-difluoropropyl)-6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308776: Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	ic50	0.4600	uM
8-(3-aminopropyl)-6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308776: Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	ic50	0.6020	uM
4-N-[5-[(1R,2R)-2-fluorocyclopropyl]-1H-pyrazol-3-yl]-2-N-[(1S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl]pyrimidine-2,4-diamine	1311587: Inhibition of PAK1/2/3 in human EBC1 cells assessed as MEK1 phosphorylation level at Serine298 residue incubated for 2 hrs by HTRF assay	ic50	0.8100	uM
(3R)-3-[[8-chloro-11-(2,2-difluoroethyl)-3-fluoro-5H-benzo[b][1,4]benzodiazepin-6-ylidene]amino]-N-propan-2-ylpyrrolidine-1-carboxamide	1935333: Inhibition of human recombinant full length PAK2 assessed as phosphorylation FRET peptide substrate measured after 60 mins	ic50	0.8240	uM
6-[2-chloro-4-(3-methyl-2-oxo-1-pyridinyl)phenyl]-8-(2-hydroxyethyl)-2-(methylamino)pyrido[2,3-d]pyrimidin-7-one	1308776: Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	ic50	0.9300	uM
8-[(4-aminocyclohexyl)methyl]-6-[2-chloro-4-(6-methylpyrazin-2-yl)phenyl]pyrido[2,3-d]pyrimidin-7-one	1308782: Inhibition of human recombinant PAK2 assessed as phosphorylation of coumarin labeled FRET peptide substrate at Ser/Thr19 preincubated for 10 mins followed by ATP addition measured after 60 mins by Z’-LYTE assay	ki	0.9400	uM
1-[2-[3-(2-aminopyrimidin-4-yl)-2-(2-methoxyethylamino)benzimidazol-5-yl]ethynyl]cyclohexan-1-ol	1074643: Inhibition of PAK2 (unknown origin)	ic50	0.9700	uM

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	4
bisphenol A	decreases methylation, increases expression	2
sodium arsenite	decreases expression, increases abundance	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Caffeine	affects phosphorylation, increases activity	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	increases expression	2
Particulate Matter	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
salinomycin	decreases expression	1
butyraldehyde	decreases expression	1
ochratoxin A	increases expression	1
coumarin	affects phosphorylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Oxaliplatin	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acetaminophen	increases expression	1
Vehicle Emissions	decreases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1

ChEMBL screening assays

376 unique, capped per target: 373 binding, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3820951	Binding	Inhibition of PAK1/2 in human EBC1 cells assessed as phosphorylation of MEK1 at serine 298 after 2 hrs by HTRF assay	Chemically Diverse Group I p21-Activated Kinase (PAK) Inhibitors Impart Acute Cardiovascular Toxicity with a Narrow Therapeutic Window. — J Med Chem
CHEMBL3865539	ADMET	Inhibition of N-terminal 6His-tagged recombinant human PAK2 (3-end residues) expressed in expressed in Escherichia coli at 100 nM	Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors. — ACS Med Chem Lett

Cellosaurus cell lines

10 cell lines: 9 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1ZT	Abcam HeLa PAK2 KO	Cancer cell line	Female
CVCL_B8LX	Abcam HCT 116 PAK2 KO	Cancer cell line	Male
CVCL_B8ZU	Abcam MCF-7 PAK2 KO	Cancer cell line	Female
CVCL_B9P3	Abcam A-549 PAK2 KO	Cancer cell line	Male
CVCL_D7WG	Ubigene A-549 PAK2 KO	Cancer cell line	Male
CVCL_D9M7	Ubigene HEK293 PAK2 KO	Transformed cell line	Female
CVCL_TB90	HAP1 PAK2 (-) 1	Cancer cell line	Male
CVCL_TB91	HAP1 PAK2 (-) 2	Cancer cell line	Male
CVCL_TB92	HAP1 PAK2 (-) 3	Cancer cell line	Male
CVCL_TB93	HAP1 PAK2 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.