PAK5

Summary

PAK5 (p21 (RAC1) activated kinase 5, HGNC:15916) is a protein-coding gene on chromosome 20p12.2, encoding Serine/threonine-protein kinase PAK 5 (Q9P286). Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, proliferation or cell survival.

The protein encoded by this gene is a member of the PAK family of Ser/Thr protein kinases. PAK family members are known to be effectors of Rac/Cdc42 GTPases, which have been implicated in the regulation of cytoskeletal dynamics, proliferation, and cell survival signaling. This kinase contains a CDC42/Rac1 interactive binding (CRIB) motif, and has been shown to bind CDC42 in the presence of GTP. This kinase is predominantly expressed in brain. It is capable of promoting neurite outgrowth, and thus may play a role in neurite development. This kinase is associated with microtubule networks and induces microtubule stabilization. The subcellular localization of this kinase is tightly regulated during cell cycle progression. Alternatively spliced transcript variants encoding the same protein have been described.

Source: NCBI Gene 57144 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 108 total
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_177990

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15916
Approved symbol	PAK5
Name	p21 (RAC1) activated kinase 5
Location	20p12.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1264
Ensembl gene	ENSG00000101349
Ensembl biotype	protein_coding
OMIM	608038
Entrez	57144

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000353224, ENST00000378423, ENST00000378429, ENST00000875443, ENST00000959437

RefSeq mRNA: 2 — MANE Select: NM_177990 NM_020341, NM_177990

CCDS: CCDS13107

Canonical transcript exons

ENST00000353224 — 10 exons

Exon	Start	End
ENSE00000659008	9565893	9566384
ENSE00000659009	9580145	9580930
ENSE00000859081	9542586	9542720
ENSE00000859082	9544369	9544494
ENSE00000859083	9557608	9557734
ENSE00001218547	9711286	9711435
ENSE00001477549	9644125	9644339
ENSE00001598137	9562891	9563024
ENSE00001901152	9838762	9839076
ENSE00003909812	9537370	9539617

Expression profiles

Bgee: expression breadth ubiquitous, 123 present calls, max score 96.45.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7162 / max 148.8639, expressed in 202 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186395	0.9383	156
186398	0.5668	111
186396	0.1651	61
186397	0.0458	29

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	96.45	gold quality
middle temporal gyrus	UBERON:0002771	91.00	gold quality
ganglionic eminence	UBERON:0004023	90.89	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.94	gold quality
cerebellar vermis	UBERON:0004720	89.55	gold quality
endothelial cell	CL:0000115	89.30	gold quality
primary visual cortex	UBERON:0002436	87.38	gold quality
Brodmann (1909) area 46	UBERON:0006483	85.64	gold quality
buccal mucosa cell	CL:0002336	84.91	gold quality
occipital lobe	UBERON:0002021	84.85	gold quality
cerebellum	UBERON:0002037	84.26	gold quality
cerebellar cortex	UBERON:0002129	83.76	gold quality
cerebellar hemisphere	UBERON:0002245	83.61	gold quality
prefrontal cortex	UBERON:0000451	82.27	gold quality
right hemisphere of cerebellum	UBERON:0014890	82.23	gold quality
entorhinal cortex	UBERON:0002728	81.98	gold quality
superior frontal gyrus	UBERON:0002661	81.33	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	79.96	gold quality
frontal cortex	UBERON:0001870	79.90	gold quality
orbitofrontal cortex	UBERON:0004167	79.80	gold quality
neocortex	UBERON:0001950	79.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	79.21	gold quality
postcentral gyrus	UBERON:0002581	78.88	gold quality
parietal lobe	UBERON:0001872	78.72	gold quality
cerebral cortex	UBERON:0000956	78.48	gold quality
lateral nuclear group of thalamus	UBERON:0002736	78.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.62	gold quality
ventricular zone	UBERON:0003053	76.23	gold quality
right frontal lobe	UBERON:0002810	75.80	gold quality
telencephalon	UBERON:0001893	75.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	59.01
E-ANND-3	yes	6.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

198 targeting PAK5, 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-4776-3P	100.00	68.73	1340
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548N	99.98	71.94	4170
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
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-6753-3P	99.93	66.57	637

Literature-anchored findings (GeneRIF, showing 39)

• PAK5 suppresses the activity of microtubule affinity-regulating kinase 2 (MARK2) toward its target, tau protein. (PMID:16014608)
• Nucleocytoplasmic shuttling of PAK7 regulates its antiapoptotic properties. (PMID:16581795)
• Study demonstrated that PAK5 expression increased significantly with malignant progression of CRC (colorectal cancer), and that PAK5 might promote CRC metastasis by regulating CRC cell adhesion and migration. (PMID:19415746)
• Data show that both Pak5 and constitutively active Pak4, the founding member of the Group B Paks, directly phosphorylate p120 in vitro. (PMID:20564219)
• PAK7 is a new hallmark of gastric cancer, PAK7 may contribute to gain of tumor growth potential, acting by affecting the expression of cell cycle regulators. (PMID:23106939)
• The PAK5-Egr1-MMP2 signaling pathway is a critical regulator of cell migration and invasion in lung cancer cells. (PMID:23696025)
• identified three kinases with gain-of-function mutations in lung cancer, namely FGFR4, MAP3K9, and PAK5. Mutations in these kinases are activating toward the ERK pathway, and targeted depletion of the mutated kinases inhibits proliferation (PMID:23836671)
• PAK5 is correlated to human epithelial ovarian cancer (EOC) and increased PAK5 expression promotes EOC progression. (PMID:23877225)
• It inhibits glioma cell migration and invasion potentially through the PAK5-Egr1-MMP2 signaling pathway. (PMID:24062079)
• Results demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity. (PMID:24474471)
• PAK5 functions as an oncogenic kinase in tumor cellular regulation (PMID:24869804)
• PAK7 promotes cell proliferation and tumorigenesis (PMID:25052921)
• Aurora-A induced PAK7 expression in esophageal cancer cells. (PMID:25436453)
• results suggest that the inhibition of PAK5 by RNA interference might efficiently suppress tumor development of glioma cells with PAK5 high expression. (PMID:25632266)
• miR-129 suppresses tumor cell growth and invasion by targeting PAK5 in hepatocellular carcinoma. (PMID:26116538)
• E47 is a novel substrate of PAK5, and PAK5-mediated phosphorylation of E47 promotes epithelial-mesenchymal transition and metastasis of colon cancer. (PMID:26212009)
• PAK7 is overexpressed in human esophageal squamous cell cancer samples and correlated with lymph node metastasis. (PMID:26682509)
• model suggests PAK5 self-association interferes with AID binding to the catalytic domain, thus maintaining its high activity. (PMID:27095851)
• These findings indicate that aberrant PAK7 expression is associated with the occurrence of metastasis and poor clinical outcomes of human colon cancer by promoting the epithelial to mesechymal transition (PMID:27323857)
• PAK7 expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)
• Data suggest expression of ECAD (E-cadherin) in bladder cancer cell lines correlates with presence of intercellular junctions and level of PAK5 (p21-activated kinase PAK5 protein) expression; endogenous PAK5 is localized to intercellular junctions and interacts with ECAD; depletion of PAK5 expression reduces integrity of intercellular junctions; PAK5 mRNA levels are reduced in bladder cancer compared with normal controls. (PMID:28232500)
• p21-activated kinase (PAK7) was identified as the putative target of miR492 in osteosarcoma (OS), and we further found a significantly inverse correlation between PAK7 and miR492 in OS specimens. (PMID:28677719)
• PAK5-mediated phosphorylation and nuclear translocation of NF-kappaB-p65 promotes breast cancer cell proliferation in vitro and in vivo (PMID:29041983)
• Mechanistic studies demonstrated that miR-106a-5p directly bound to the 3’-UTR of the PAK5 mRNA and mediated a decrease in the protein expression of PAK5. (PMID:29072688)
• The PAK5 is a novel prognostic indicator and plays an important role in the cervical cancer metastasis. (PMID:30082769)
• PAK5 Induces EMT and Promotes Cell Migration and Invasion by Activating the PI3K/AKT Pathway in Ovarian Cancer. (PMID:30245957)
• Prognostic significance of PAK family kinases in acute myeloid leukemia. (PMID:30890765)
• PAK5 structure, expression, signalling pathway and function in cancer.[review] (PMID:31805288)
• Long non-coding RNA SOX21-AS1 promotes cell proliferation and invasion through upregulating PAK7 expression by sponging miR-144-3p in glioma cells. (PMID:31973536)
• Bioinformatic analysis of the potential molecular mechanism of PAK7 expression in glioblastoma. (PMID:32626960)
• PAK5 promotes the cell stemness ability by phosphorylating SOX2 in lung squamous cell carcinomas. (PMID:32721391)
• P21-activated kinase 5 potentiates the chemoresistant phenotype of liver cancer. (PMID:33542180)
• MiR-145-5p modulates lipid metabolism and M2 macrophage polarization by targeting PAK7 and regulating beta-catenin signaling in hyperlipidemia. (PMID:34143694)
• Inhibiting p21-activated kinase (PAK7) enhances radiosensitivity in hepatocellular carcinoma. (PMID:34165002)
• PAK5-stabilized Smuc confers renal cell carcinoma metastasis. (PMID:34586742)
• PAK5 promotes RNA helicase DDX5 sumoylation and miRNA-10b processing in a kinase-dependent manner in breast cancer. (PMID:34936874)
• The Predictive Value of PAK7 Mutation for Immune Checkpoint Inhibitors Therapy in Non-Small Cell Cancer. (PMID:35242138)
• PAK5 is a potential target in myelodysplastic syndrome through interacting with LMO2 and GATA1. (PMID:36905268)
• PAK5 potentiates slug transactivation of N-cadherin to facilitate metastasis of renal cell carcinoma. (PMID:37437827)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pak5	ENSDARG00000030154
mus_musculus	Pak5	ENSMUSG00000039913
rattus_norvegicus	Pak5	ENSRNOG00000005509

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), 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), PAK2 (ENSG00000180370), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Serine/threonine-protein kinase PAK 5 — Q9P286 (reviewed: Q9P286)

Alternative names: p21-activated kinase 5, p21-activated kinase 7

All UniProt accessions (1): Q9P286

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 migration, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates the proto-oncogene RAF1 and stimulates its kinase activity. Promotes cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Phosphorylates CTNND1, probably to regulate cytoskeletal organization and cell morphology. Keeps microtubules stable through MARK2 inhibition and destabilizes the F-actin network leading to the disappearance of stress fibers and focal adhesions.

Subunit / interactions. Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Interacts with MARK2, leading to inhibit MARK2 independently of kinase activity. Interacts with RHOD and RHOH.

Subcellular location. Mitochondrion. Cytoplasm. Nucleus.

Tissue specificity. Predominantly expressed in brain.

Post-translational modifications. Autophosphorylated when activated by CDC42/p21.

Domain organisation. An autoinhibitory domain is present in the N-terminal region of the protein.

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

RefSeq proteins (2): NP_065074, NP_817127* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000095	CRIB_dom	Domain
IPR000719	Prot_kinase_dom	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR028754	STKc_PAK5	Domain
IPR033923	PAK_BD	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)
• EC 2.7.12.2 — mitogen-activated protein kinase kinase (BRENDA: 38 organisms, 149 substrates, 134 inhibitors, 6 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. 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
ATP	0.0533	1
ERK2	0.0002	1
K52R-[ERK2]	0.0001	1
K53M-[P38ALPHA]	0.0002	1
P38ALPHA	0.0002	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 (55 total): helix 18, sequence variant 9, strand 8, region of interest 5, domain 2, binding site 2, modified residue 2, sequence conflict 2, turn 2, compositionally biased region 2, chain 1, active site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8C12	X-RAY DIFFRACTION	1.55
2F57	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P286-F1	63.09	0.36

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 (1): 568 (proton acceptor)

Ligand- & substrate-binding residues (2): 455–463; 478

Post-translational modifications (2): 104, 107

Mutagenesis-validated functional residues (1):

Position	Phenotype
19–22	complete loss of cdc42 binding and cdc42-mediated autophosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-428540	Activation of RAC1
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013407	RHOH GTPase cycle

MSigDB gene sets: 220 (showing top): GOBP_MEMORY, GOBP_COGNITION, GOBP_BEHAVIOR, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, AAGCCAT_MIR135A_MIR135B, GOBP_GROWTH, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, TATTATA_MIR374, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, CAGCTG_AP4_Q5, ATGTTAA_MIR302C, GOBP_NEGATIVE_REGULATION_OF_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, KEGG_ERBB_SIGNALING_PATHWAY, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_LEARNING

GO Biological Process (14): regulation of cell growth (GO:0001558), apoptotic process (GO:0006915), cytoskeleton organization (GO:0007010), signal transduction (GO:0007165), learning (GO:0007612), memory (GO:0007613), locomotory behavior (GO:0007626), cell population proliferation (GO:0008283), cellular response to starvation (GO:0009267), cell migration (GO:0016477), intracellular signal transduction (GO:0035556), regulation of MAPK cascade (GO:0043408), negative regulation of extrinsic apoptotic signaling pathway (GO:2001237), protein phosphorylation (GO:0006468)

GO Molecular Function (8): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (8): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), nuclear membrane (GO:0031965), synapse (GO:0045202), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	4
Signaling by ROBO receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cellular process	2
learning or memory	2
intracellular anatomical structure	2
protein kinase activity	2
cytoplasm	2
intracellular membrane-bounded organelle	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
organelle organization	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
behavior	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
cell motility	1
signal transduction	1
MAPK cascade	1
regulation of intracellular signal transduction	1
extrinsic apoptotic signaling pathway	1
negative regulation of apoptotic signaling pathway	1
regulation of extrinsic apoptotic signaling pathway	1
phosphorylation	1
protein modification process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1

Protein interactions and networks

STRING

1912 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAK5	CDC42	P21181	879
PAK5	ARHGEF25	Q86VW2	669
PAK5	RHOA	P06749	608
PAK5	AR	P10275	582
PAK5	RHOG	P35238	544
PAK5	NGEF	Q8N5V2	486
PAK5	MARK2	Q7KZI7	464
PAK5	SYDE1	Q6ZW31	460
PAK5	PAK4	O96013	460
PAK5	MFN2	O95140	416
PAK5	PAK6	Q9NQU5	415
PAK5	NCK1	P16333	409
PAK5	AKT1	P31749	402
PAK5	CUL1	Q13616	391
PAK5	WT1	P19544	381

IntAct

161 interactions, top by confidence:

A	B	Type	Score
PAK5	ATPAF2	psi-mi:“MI:0915”(physical association)	0.780
ATPAF2	PAK5	psi-mi:“MI:0915”(physical association)	0.780
CDC42	PAK5	psi-mi:“MI:0915”(physical association)	0.740
PRPF31	PAK5	psi-mi:“MI:0915”(physical association)	0.720
PAK5	INKA1	psi-mi:“MI:0915”(physical association)	0.700
INKA1	PAK5	psi-mi:“MI:0915”(physical association)	0.700
PAK5	CCNG1	psi-mi:“MI:0915”(physical association)	0.670
PAK5	CRBN	psi-mi:“MI:0915”(physical association)	0.670
CARD9	PAK5	psi-mi:“MI:0915”(physical association)	0.670
UXT	PAK5	psi-mi:“MI:0915”(physical association)	0.670
CCNG1	PAK5	psi-mi:“MI:0915”(physical association)	0.670
CRBN	PAK5	psi-mi:“MI:0915”(physical association)	0.670
PAK5	CARD9	psi-mi:“MI:0915”(physical association)	0.670
PAK5	UXT	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (152): PAK7 (Two-hybrid), PAK7 (Two-hybrid), PAK7 (Two-hybrid), PAK7 (Two-hybrid), PAK7 (Two-hybrid), PAK7 (Two-hybrid), CARD9 (Two-hybrid), LENG1 (Two-hybrid), GCC1 (Two-hybrid), ARMC7 (Two-hybrid), ATPAF2 (Two-hybrid), FAM212A (Two-hybrid), PAK7 (Affinity Capture-MS), PAK7 (Two-hybrid), PAK7 (Two-hybrid)

ESM2 similar proteins: A0A1L8F1M4, A2CEX1, A8DZE6, A8WH69, A9LS46, B1AZP2, B5DEH0, D4A280, E7FDW2, E9Q0S6, G5E5X0, O14490, O94875, P49023, P97836, P97837, P97839, Q04205, Q28FG2, Q3U5C7, Q5DTV4, Q5HYM0, Q5R7I1, Q5RFW2, Q5SSZ5, Q5XI07, Q66H76, Q6ZMN7, Q71QF9, Q7T2V3, Q7Z3G6, Q7ZYZ6, Q80Y24, Q8BJ42, Q8C015, Q8IYT8, Q8VI36, Q90WV2, Q90Z06, Q96MT3

Diamond homologs: A0A194W8T8, A0A8I5ZNK2, A7A1P0, A9SY39, B0XXN8, B5DFG1, B5VNQ3, C4YRB7, D4A280, D6WMX4, E0W1I1, F4JBP3, G4N7X0, G4NDR3, O14328, O22042, O35099, O88506, O95382, O95747, O96013, P0CY23, P0CY24, P22216, P23561, P28829, P54265, P83510, Q03497, Q04759, Q09013, Q09298, Q09792, Q0KHV6, Q10407, Q15835, Q21029, Q40541, Q4P5N0, Q4WHP3

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
PAK5	“down-regulates quantity by destabilization”	DNPEP	phosphorylation
PAK5	“up-regulates activity”	TCF3	phosphorylation
PAK5	“up-regulates activity”	GATA1	phosphorylation
PAK5	“up-regulates activity”	RELA	phosphorylation
PAK5	“up-regulates quantity by stabilization”	DDX5	phosphorylation
PAK5	“down-regulates activity”	AIFM1	phosphorylation
PAK5	“down-regulates activity”	BAD	phosphorylation
PAK5	“up-regulates activity”	PAK5	phosphorylation
PAK5	“up-regulates activity”	PACSIN1	phosphorylation
PAK5	“up-regulates activity”	SYNJ1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 68 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
Activation of BAD and translocation to mitochondria	5	73.2×	9e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	64.6×	9e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	64.6×	9e-07
Activation of BH3-only proteins	5	47.7×	4e-06
RHO GTPases activate PKNs	5	30.5×	3e-05
Intrinsic Pathway for Apoptosis	5	28.2×	4e-05
SARS-CoV-1-host interactions	5	16.9×	4e-04
Apoptosis	5	16.1×	4e-04

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	6	10.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	92
Likely benign	2
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

3159 predictions. Top by Δscore:

Variant	Effect	Δscore
20:9542580:TCTCA:T	donor_loss	1.0000
20:9542581:CTCA:C	donor_loss	1.0000
20:9542582:TCA:T	donor_loss	1.0000
20:9542583:CA:C	donor_loss	1.0000
20:9542585:CCTT:C	donor_loss	1.0000
20:9560181:T:TA	donor_gain	1.0000
20:9562921:C:CT	donor_gain	1.0000
20:9562922:C:CT	donor_gain	1.0000
20:9565887:CTTTA:C	donor_loss	1.0000
20:9565889:TTA:T	donor_loss	1.0000
20:9565891:A:AT	donor_loss	1.0000
20:9565892:CC:C	donor_loss	1.0000
20:9580926:ATTGT:A	acceptor_gain	1.0000
20:9580927:TTGT:T	acceptor_gain	1.0000
20:9580928:TGT:T	acceptor_gain	1.0000
20:9580929:GT:G	acceptor_gain	1.0000
20:9580930:TC:T	acceptor_loss	1.0000
20:9580931:C:CC	acceptor_gain	1.0000
20:9580931:C:CG	acceptor_loss	1.0000
20:9580937:A:AC	acceptor_gain	1.0000
20:9580940:A:AC	acceptor_gain	1.0000
20:9580940:A:C	acceptor_gain	1.0000
20:9644120:CATAC:C	donor_loss	1.0000
20:9644122:TA:T	donor_loss	1.0000
20:9644123:A:AG	donor_loss	1.0000
20:9644124:CCT:C	donor_loss	1.0000
20:9720166:T:A	donor_gain	1.0000
20:9838760:AC:A	donor_loss	1.0000
20:9838761:C:G	donor_loss	1.0000
20:9557601:ATCTT:A	donor_loss	0.9900

AlphaMissense

4739 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:9539558:T:A	R688S	1.000
20:9539558:T:G	R688S	1.000
20:9539559:C:G	R688T	1.000
20:9542635:A:G	M652T	1.000
20:9542668:G:C	P641R	1.000
20:9542668:G:T	P641H	1.000
20:9542669:G:A	P641S	1.000
20:9542683:A:C	M636R	1.000
20:9542683:A:T	M636K	1.000
20:9542685:T:A	E635D	1.000
20:9542685:T:G	E635D	1.000
20:9542686:T:A	E635V	1.000
20:9542687:C:T	E635K	1.000
20:9542695:A:C	M632R	1.000
20:9542695:A:T	M632K	1.000
20:9542701:C:T	G630E	1.000
20:9542702:C:A	G630W	1.000
20:9542702:C:G	G630R	1.000
20:9542702:C:T	G630R	1.000
20:9542704:A:G	L629P	1.000
20:9542709:C:A	W627C	1.000
20:9542709:C:G	W627C	1.000
20:9542711:A:G	W627R	1.000
20:9542711:A:T	W627R	1.000
20:9542716:T:A	D625V	1.000
20:9542716:T:G	D625A	1.000
20:9542717:C:A	D625Y	1.000
20:9542717:C:G	D625H	1.000
20:9544394:A:T	I615N	1.000
20:9544409:A:C	M610R	1.000

dbSNP variants (sampled 300 via entrez): RS1000009596 (20:9757951 G>A), RS1000013323 (20:9653781 T>A,G), RS1000033388 (20:9834136 A>T), RS1000055140 (20:9702028 T>C), RS1000076794 (20:9806357 G>T), RS1000085704 (20:9701639 A>G,T), RS1000086158 (20:9724701 T>A,C), RS1000113297 (20:9751677 C>T), RS1000124260 (20:9630710 C>A,T), RS1000132275 (20:9595776 T>G), RS1000146660 (20:9744617 C>T), RS1000152037 (20:9715373 G>A), RS1000157416 (20:9677108 G>C,T), RS1000164857 (20:9722152 G>A), RS1000172856 (20:9635659 A>C)

Disease associations

OMIM: gene MIM:608038 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001762_40	Obesity-related traits	8.000000e-06
GCST002874_33	Psoriasis	1.000000e-06
GCST003075_5	Cognitive decline rate in late mild cognitive impairment	9.000000e-07
GCST003075_63	Cognitive decline rate in late mild cognitive impairment	3.000000e-07
GCST006956_15	Erectile dysfunction	7.000000e-06
GCST009303_5	Abstraction and mental flexibility	7.000000e-07
GCST010149_1	Brain imaging measurements (variance)	2.000000e-08
GCST010278_3	Hand grip strength (Mahalanobis distance)	1.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0009332	executive function measurement
EFO:0004346	neuroimaging measurement
EFO:0006941	grip strength measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4524 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 109,705 (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
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL603469	LESTAURTINIB	3
CHEMBL1721885	SU-014813	2	363
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 — PAKB subfamily

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
compound 4 [PMID: 24432870]	Inhibition	7.44	pIC50
GSK690693	Inhibition	7.28	pIC50
AMG28	Inhibition	7.02	pIC50
PF-3758309	Inhibition	6.77	pIC50

Binding affinities (BindingDB)

6 measured of 7 human assays (7 total across all organisms); most potent 6 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
BIIB-057	IC50	10.5 nM
CPR005231 (6)	IC50	247 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
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM

ChEMBL bioactivities

41 potent at pChembl≥5 of 41 total, top 35 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.92	Kd	1.2	nM	STAUROSPORINE
8.60	IC50	2.53	nM	STAUROSPORINE
8.52	Kd	3	nM	STAUROSPORINE
8.43	IC50	3.76	nM	STAUROSPORINE
8.28	IC50	5.3	nM	STAUROSPORINE
8.05	Kd	8.9	nM	GSK-690693
7.92	Kd	12	nM	CHEMBL3416026
7.82	IC50	15	nM	CHEMBL4097816
7.74	IC50	18.1	nM	PF-03758309
7.74	Ki	18.1	nM	PF-03758309
7.62	Kd	24	nM	LESTAURTINIB
7.40	Kd	40	nM	CHEMBL4465866
7.28	Kd	53	nM	CHEMBL4576489
7.28	IC50	52	nM	GSK-690693
7.16	Kd	69	nM	R-406
7.02	IC50	96	nM	CHEMBL2334586
6.90	IC50	126	nM	CHEMBL3128042
6.78	IC50	166	nM	CHEMBL2177736
6.41	Kd	390	nM	TAE-684
6.41	Kd	390	nM	KW-2449
6.39	Kd	410	nM	CHEMBL1908395
6.30	Ki	500	nM	SUNITINIB
6.28	Kd	520	nM	CHEMBL1241674
6.19	Kd	640	nM	SUNITINIB
6.17	Kd	670	nM	CHEMBL379218
6.08	Kd	830	nM	JNJ-7706621
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.92	Kd	1200	nM	FEDRATINIB
5.89	Kd	1300	nM	SU-014813
5.89	Kd	1300	nM	RUXOLITINIB
5.89	Kd	1300	nM	NINTEDANIB
5.58	Kd	2600	nM	PHA-665752
5.48	Kd	3300	nM	TOZASERTIB

PubChem BioAssay actives

37 with measured affinity, of 962 total; 25 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
(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	435687: Binding constant for PAK7/PAK5 kinase domain	kd	0.0012	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	625117: Binding constant for PAK7 kinase domain	kd	0.0089	uM
3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-(1H-indol-7-ylamino)-1,2,4-triazine-6-carboxamide	1199671: Competitive binding affinity to human PAK7	kd	0.0120	uM
[6-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]quinazolin-2-yl]-[(3R)-3-methylpiperazin-1-yl]methanone	1478230: Inhibition of full length recombinant human His-tagged PAK5 (295 to 591 residues) expressed in Baculovirus expression system by Z’-Lyte assay	ic50	0.0150	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	1242469: Inhibition of PAK5 (unknown origin) using peptide 7 as substrate by pyruvate kinase/lactate dehydrogenase coupled assay	ic50	0.0181	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	507661: Binding affinity to PAK7	kd	0.0240	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526197: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged PAK7 (unknown origin) (425 to 719 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0400	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-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-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526197: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged PAK7 (unknown origin) (425 to 719 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.0530	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	625117: Binding constant for PAK7 kinase domain	kd	0.0690	uM
4-(4-amino-3,5,12-triazatetracyclo[9.7.0.02,7.013,18]octadeca-1(11),2,4,6,13(18),14,16-heptaen-16-yl)-2-methylbut-3-yn-2-ol	1856575: Inhibition of human wild type partial length PAK5 (Y400 to H719 residues) expressed in bacterial expression system by Kinomescan assay	ic50	0.0960	uM
1-[2-[3-(2-aminopyrimidin-4-yl)-2-(2-methoxyethylamino)benzimidazol-5-yl]ethynyl]cyclohexan-1-ol	1074641: Inhibition of PAK5 (unknown origin)	ic50	0.1260	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625117: Binding constant for PAK7 kinase domain	kd	0.3900	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	625117: Binding constant for PAK7 kinase domain	kd	0.3900	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625117: Binding constant for PAK7 kinase domain	kd	0.4100	uM
Sunitinib	1453240: Inhibition of PAK5 (unknown origin)	ki	0.5000	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	625117: Binding constant for PAK7 kinase domain	kd	0.5200	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	625117: Binding constant for PAK7 kinase domain	kd	0.6700	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435687: Binding constant for PAK7/PAK5 kinase domain	kd	0.8300	uM
Fedratinib	625117: Binding constant for PAK7 kinase domain	kd	1.2000	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	625117: Binding constant for PAK7 kinase domain	kd	1.3000	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625117: Binding constant for PAK7 kinase domain	kd	1.3000	uM
Ruxolitinib	625117: Binding constant for PAK7 kinase domain	kd	1.3000	uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one	625117: Binding constant for PAK7 kinase domain	kd	2.6000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	435687: Binding constant for PAK7/PAK5 kinase domain	kd	3.3000	uM
N-[2-(dimethylamino)ethyl]-3-[2-(4-hydroxy-3-methoxyphenyl)pyrrolo[1,2-b]pyridazin-7-yl]benzamide	1801000: DAPK1 Electrophoretic Mobility Shift Assay from Article 10.1002/cbic.201402512: “Identification and characterization of a small-molecule inhibitor of death-associated protein kinase 1.”	ic50	5.6000	uM

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	3
Valproic Acid	increases expression, affects expression, affects cotreatment	3
Aflatoxin B1	decreases expression, decreases methylation	3
lasiocarpine	decreases expression	2
methyleugenol	decreases expression	2
clothianidin	decreases expression	2
N-Nitrosopyrrolidine	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
trichostatin A	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
Acetaminophen	increases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Cyclosporine	decreases methylation	1

ChEMBL screening assays

217 unique, capped per target: 217 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003341	Binding	Inhibition of PAK5 at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem

Clinical trials (associated diseases)

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