PAK6

Summary

PAK6 (p21 (RAC1) activated kinase 6, HGNC:16061) is a protein-coding gene on chromosome 15q15.1, encoding Serine/threonine-protein kinase PAK 6 (Q9NQU5). Serine/threonine protein kinase that plays a role in the regulation of gene transcription.

This gene encodes a member of a family of p21-stimulated serine/threonine protein kinases, which contain an amino-terminal Cdc42/Rac interactive binding (CRIB) domain and a carboxyl-terminal kinase domain. These kinases function in a number of cellular processes, including cytoskeleton rearrangement, apoptosis, and the mitogen-activated protein (MAP) kinase signaling pathway. The protein encoded by this gene interacts with androgen receptor (AR) and translocates to the nucleus, where it is involved in transcriptional regulation. Changes in expression of this gene have been linked to prostate cancer. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 56924 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 111 total
• Druggable target: yes — 13 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001395430

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16061
Approved symbol	PAK6
Name	p21 (RAC1) activated kinase 6
Location	15q15.1
Locus type	gene with protein product
Status	Approved
Aliases	PAK5
Ensembl gene	ENSG00000137843
Ensembl biotype	protein_coding
OMIM	608110
Entrez	56924

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 31 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000260404, ENST00000441369, ENST00000453867, ENST00000455577, ENST00000542403, ENST00000557808, ENST00000557926, ENST00000558055, ENST00000558106, ENST00000558183, ENST00000558658, ENST00000558878, ENST00000559139, ENST00000559617, ENST00000559901, ENST00000560346, ENST00000560669, ENST00000560684, ENST00000560806, ENST00000561230, ENST00000880989, ENST00000880990, ENST00000880991, ENST00000880992, ENST00000880993, ENST00000880994, ENST00000912880, ENST00000912881, ENST00000912882, ENST00000957933, ENST00000957934, ENST00000957935, ENST00000957936, ENST00000957937

RefSeq mRNA: 7 — MANE Select: NM_001395430 NM_001128628, NM_001128629, NM_001276717, NM_001276718, NM_001395430, NM_001395431, NM_020168

CCDS: CCDS61590

Canonical transcript exons

ENST00000560346 — 11 exons

Exon	Start	End
ENSE00003851269	40274142	40274276
ENSE00003854628	40253178	40253289
ENSE00003855670	40272866	40272999
ENSE00003856913	40240599	40240681
ENSE00003862226	40264781	40264989
ENSE00003866087	40273346	40273472
ENSE00003871542	40273551	40273676
ENSE00003885593	40272224	40272721
ENSE00003887139	40265842	40266495
ENSE00003978345	40275927	40277487
ENSE00003978346	40239063	40239802

Expression profiles

Bgee: expression breadth ubiquitous, 212 present calls, max score 91.85.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5901 / max 118.8066, expressed in 571 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
146074	0.7519	122
146084	0.6348	297
146076	0.3603	137
146075	0.2376	116
146079	0.1630	86
146078	0.1374	78
146083	0.1157	67
146080	0.0693	47
146077	0.0389	21
146081	0.0376	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	91.85	gold quality
gingiva	UBERON:0001828	90.15	gold quality
entorhinal cortex	UBERON:0002728	89.36	gold quality
right frontal lobe	UBERON:0002810	89.28	gold quality
upper leg skin	UBERON:0004262	89.27	gold quality
prefrontal cortex	UBERON:0000451	89.03	gold quality
skin of leg	UBERON:0001511	88.93	gold quality
frontal cortex	UBERON:0001870	88.58	gold quality
postcentral gyrus	UBERON:0002581	88.28	gold quality
esophagus mucosa	UBERON:0002469	88.25	gold quality
skin of abdomen	UBERON:0001416	88.24	gold quality
superior frontal gyrus	UBERON:0002661	88.22	gold quality
anterior cingulate cortex	UBERON:0009835	88.05	gold quality
cingulate cortex	UBERON:0003027	87.98	gold quality
middle temporal gyrus	UBERON:0002771	87.88	gold quality
neocortex	UBERON:0001950	87.79	gold quality
zone of skin	UBERON:0000014	87.52	gold quality
primary visual cortex	UBERON:0002436	87.29	gold quality
lower esophagus mucosa	UBERON:0035834	87.19	gold quality
parietal lobe	UBERON:0001872	87.13	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	87.04	gold quality
temporal lobe	UBERON:0001871	86.99	gold quality
nucleus accumbens	UBERON:0001882	86.94	gold quality
endothelial cell	CL:0000115	86.63	gold quality
cerebral cortex	UBERON:0000956	86.42	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.39	gold quality
esophagus squamous epithelium	UBERON:0006920	86.21	gold quality
epithelium of esophagus	UBERON:0001976	85.94	gold quality
cerebellar hemisphere	UBERON:0002245	85.93	gold quality
cerebellar cortex	UBERON:0002129	85.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.73

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting PAK6, 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-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-4777-5P	99.33	67.53	1148
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-6841-3P	98.08	66.54	604
HSA-MIR-10397-5P	97.31	69.06	710
HSA-MIR-4750-3P	96.65	64.38	512

Literature-anchored findings (GeneRIF, showing 24)

• The activation of PAK6 by both p38 MAP kinase and MKK6 suggests that PAK6 plays a role in the cellular response to stress-related signals. (PMID:15550393)
• Results indicate that all of the 3 prostate cancer specimens showed positive staining in the stroma, suggesting that PAK6 may participate in the stroma-cancer cell interaction in prostate cancer. (PMID:17584649)
• PAK5 is a potent regulator of Raf-1 activity and may control Raf-1 dependent signaling at mitochondria (PMID:18465753)
• PAK6 was weakly expressed in normal prostate epithelium. Its expression was increased in primary and metastatic prostate cancer, and was further increased in tumors that relapsed after androgen deprivation therapy. (PMID:18642328)
• Hypermethylation of PAK6 gene is associated with adenocarcinoma. (PMID:20524398)
• PAK6 phosphorylates Mdm2 on Thr-158 and Ser-186, which is critical for AR ubiquitin-mediated degradation. (PMID:23132866)
• PAK5 plays an essential role in the initiation and progression of hepatocellular carcinoma. (PMID:23685956)
• These results demonstrate that androgen-stimulated PAK6 activation is mediated through a direct interaction between AR and PAK6 and PAK6 activation promotes prostate cancer cells motility and invasion. (PMID:24130878)
• PAK6 is specifically required for carcinoma cell-cell dissociation downstream of hepatocyte growth factor (HGF) for both DU145 prostate cancer and HT29 colon cancer cells. (PMID:24352566)
• PAK6 is overexpressed in hepatocellular carcinoma, compared with the adjacent noncancerous liver tissues, and is associated with poor prognosis. (PMID:24576777)
• we report that in colon cancer PAK6 promotes tumor progression and chemoresistance both in vitro and in vivo (PMID:25426562)
• the results of the present study suggested that miR-429 inhibits the migration and invasion of colon cancer cells, partly at least, by mediating the expression of PAK6, as well as the activity of cofilin signaling (PMID:26058485)
• p21-activated kinase 6 (PAK6) as a novel interactor of leucine-rich repeat kinase 2 (LRRK2), a kinase involved in Parkinson’s disease (PMID:26375402)
• negative correlation between PAK6 and EZH2 expression was observed in hepatoma tissues from HCC patients. These data identified the tumor suppressive role and potential underlying mechanism of PAK6 in hepatocarcinogenesis (PMID:26442588)
• PAK6 is directly targeted by miR-328. miR-328 inhibits cell growth and promotes cell apoptosis in prostate cancer cells. (PMID:26459798)
• PAK6 localization to cell-cell adhesions is Cdc42-dependent (PMID:26598554)
• inhibition of PAK6 leads to reduction in cell proliferation, migration and invasion of cigarette smoke treated non-small cell lung cancer cells (PMID:27542207)
• RhoD recruits Pak6 to the plasma membrane to antagonize RhoC signaling during cell contraction and blebbing (PMID:28486133)
• Study shows that high PAK6 expression is associated with poor prognosis and increased chemoresistance to 5-FU/oxaliplatin chemotherapy of gastric tumor. (PMID:28687498)
• Mitochondrial PAK6 inhibits prostate cancer cell apoptosis via the PAK6-SIRT4-ANT2 complex. (PMID:32194820)
• The miR-185/PAK6 axis predicts therapy response and regulates survival of drug-resistant leukemic stem cells in CML. (PMID:32270193)
• p21-activated kinase 6 controls mitosis and hepatocellular carcinoma progression by regulating Eg5. (PMID:33098954)
• Long non-coding RNA LINC00680 functions as a ceRNA to promote esophageal squamous cell carcinoma progression through the miR-423-5p/PAK6 axis. (PMID:35255921)
• The role of the miR-4306/PAK6 axis in degenerative nucleus pulposus cells in human intervertebral disc degeneration. (PMID:36423859)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pak6a	ENSDARG00000027564
danio_rerio	pak6b	ENSDARG00000052405
mus_musculus	Pak6	ENSMUSG00000074923
rattus_norvegicus	Pak6	ENSRNOG00000007925

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), 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 6 — Q9NQU5 (reviewed: Q9NQU5)

Alternative names: PAK-5, p21-activated kinase 6

All UniProt accessions (11): Q9NQU5, H0YK38, H0YK74, H0YK91, H0YKB6, H0YL02, H0YL16, H0YL47, H0YLZ9, H0YM99, H0YMS4

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine protein kinase that plays a role in the regulation of gene transcription. The kinase activity is induced by various effectors including AR or MAP2K6/MAPKK6. Phosphorylates the DNA-binding domain of androgen receptor/AR and thereby inhibits AR-mediated transcription. Also inhibits ESR1-mediated transcription. May play a role in cytoskeleton regulation by interacting with IQGAP1. May protect cells from apoptosis through phosphorylation of BAD.

Subunit / interactions. Interacts tightly with GTP-bound but not GDP-bound CDC42/p21 and RAC1. Interacts with the androgen receptor AR and the estrogen receptor ESR1. Interacts with IQGAP1 and PPM1B.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Selectively expressed in brain and testis, with lower levels in multiple tissues including prostate and breast.

Post-translational modifications. Autophosphorylated. Phosphorylated by MAP2K6//MAPKK6, leading to PAK6 activation.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NQU5-1	1	yes
Q9NQU5-2	2

RefSeq proteins (7): NP_001122100, NP_001122101, NP_001263646, NP_001263647, NP_001382359, NP_001382360, NP_064553 (=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
IPR033923	PAK_BD	Domain
IPR035066	STKc_PAK6	Domain
IPR036936	CRIB_dom_sf	Homologous_superfamily
IPR051931	PAK3-like	Family

Pfam: PF00069, PF00786

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 (67 total): helix 18, sequence variant 13, strand 10, region of interest 5, turn 5, compositionally biased region 3, mutagenesis site 3, domain 2, binding site 2, sequence conflict 2, chain 1, active site 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4KS7	X-RAY DIFFRACTION	1.4
2C30	X-RAY DIFFRACTION	1.6
6QDR	X-RAY DIFFRACTION	1.61
6QDS	X-RAY DIFFRACTION	1.72
4KS8	X-RAY DIFFRACTION	1.95
2ODB	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQU5-F1	67.01	0.40

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): 526 (proton acceptor)

Ligand- & substrate-binding residues (2): 413–421; 436

Post-translational modifications (1): 560

Mutagenesis-validated functional residues (3):

Position	Phenotype
165	almost complete loss of pak6 activation by map2k6/mapkk6; when associated with f-566.
560	complete loss of pak6 activation by map2k6/mapkk6; when associated with a-165.
566	complete loss of pak6 activation by map2k6/mapkk6; when associated with a-165.

Function

Pathways and Gene Ontology

Reactome pathways

6 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
R-HSA-9013424	RHOV GTPase cycle

MSigDB gene sets: 391 (showing top): GOBP_MEMORY, FXR_IR1_Q6, GOBP_COGNITION, MYOGENIN_Q6, GOBP_BEHAVIOR, GOBP_NEURON_PROJECTION_EXTENSION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, JAEGER_METASTASIS_DN, TGCACTT_MIR519C_MIR519B_MIR519A, PEREZ_TP63_TARGETS, AAGCCAT_MIR135A_MIR135B, GOBP_GROWTH, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, TATTATA_MIR374, AREB6_01

GO Biological Process (12): regulation of DNA-templated transcription (GO:0006355), apoptotic process (GO:0006915), cytoskeleton organization (GO:0007010), learning (GO:0007612), memory (GO:0007613), locomotory behavior (GO:0007626), cellular response to starvation (GO:0009267), intracellular signal transduction (GO:0035556), regulation of MAPK cascade (GO:0043408), neuron projection arborization (GO:0140058), neuron projection extension (GO:1990138), protein phosphorylation (GO:0006468)

GO Molecular Function (9): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), cadherin binding (GO:0045296), 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 (7): fibrillar center (GO:0001650), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), postsynaptic density (GO:0014069), cell junction (GO:0030054), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RHO GTPase cycle	5
Signaling by ROBO receptors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
learning or memory	2
intracellular anatomical structure	2
neuron projection morphogenesis	2
protein kinase activity	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
organelle organization	1
behavior	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
signal transduction	1
MAPK cascade	1
regulation of intracellular signal transduction	1
developmental cell growth	1
developmental growth involved in morphogenesis	1
phosphorylation	1
protein modification process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cell adhesion molecule 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
catalytic activity	1
nucleolus	1
nuclear lumen	1
cytoplasm	1
asymmetric synapse	1
postsynaptic specialization	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2142 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAK6	CDC42	P21181	971
PAK6	AR	P10275	903
PAK6	IQGAP1	P46940	657
PAK6	RHOV	Q96L33	616
PAK6	ARHGEF7	Q14155	608
PAK6	RHOD	O00212	548
PAK6	CDH1	P12830	534
PAK6	LRRK2	Q5S007	534
PAK6	RHOH	Q15669	529
PAK6	CTNNB1	P35222	518
PAK6	TBPL1	P62380	514
PAK6	RAC1	P15154	494
PAK6	NCK1	P16333	470
PAK6	AKT1	P31749	465
PAK6	PAK4	O96013	465

IntAct

47 interactions, top by confidence:

A	B	Type	Score
PAK4	YWHAZ	psi-mi:“MI:0914”(association)	0.920
YWHAE	PAK6	psi-mi:“MI:0915”(physical association)	0.740
PAK6	RHOJ	psi-mi:“MI:0915”(physical association)	0.670
RHOJ	PAK6	psi-mi:“MI:0915”(physical association)	0.670
PAK6	YWHAG	psi-mi:“MI:0914”(association)	0.640
PAK6	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.620
RHOV	PAK6	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	PAK6	psi-mi:“MI:0915”(physical association)	0.560
PTPRD	PAK6	psi-mi:“MI:0407”(direct interaction)	0.440
PAK6	DAPK1	psi-mi:“MI:0407”(direct interaction)	0.440
Ogn	PAK6	psi-mi:“MI:0407”(direct interaction)	0.440
PKM	PAK6	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PAK6	LRRK1	psi-mi:“MI:0407”(direct interaction)	0.440
SFN	PAK6	psi-mi:“MI:0915”(physical association)	0.400
LRRC45	PAK6	psi-mi:“MI:0915”(physical association)	0.400
ANXA6	PAK6	psi-mi:“MI:0915”(physical association)	0.400
PAK6	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.400
PAK6	CDK1	psi-mi:“MI:0915”(physical association)	0.370
PAK6	SNX2	psi-mi:“MI:0915”(physical association)	0.370
TPD52L1	PAK6	psi-mi:“MI:0915”(physical association)	0.370
PAK6	SEMA3B	psi-mi:“MI:0915”(physical association)	0.370
NEK6	PAK6	psi-mi:“MI:0915”(physical association)	0.370
MAPK14	PAK6	psi-mi:“MI:0915”(physical association)	0.370
PAK4	ARHGEF11	psi-mi:“MI:0914”(association)	0.350
CDC42		psi-mi:“MI:0914”(association)	0.350

BioGRID (102): RAC1 (Affinity Capture-Luminescence), RHOJ (Two-hybrid), PAK6 (Affinity Capture-MS), PAK6 (Reconstituted Complex), PAK6 (Reconstituted Complex), PAK6 (Two-hybrid), PAK6 (Proximity Label-MS), PAK6 (Affinity Capture-MS), YWHAG (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), YWHAE (Affinity Capture-MS), PAK6 (Affinity Capture-MS), PAK6 (Biochemical Activity), PAK6 (Reconstituted Complex), PAK6 (Reconstituted Complex)

ESM2 similar proteins: A4IFM7, A8C984, B6D5P1, B6D5P6, E9PT87, O08815, O54988, O55092, O70551, O88831, P00519, P00520, P00521, P07313, P0C865, P13234, P20689, P42684, P46087, Q13164, Q14028, Q16566, Q2KI23, Q32MK0, Q3SYS4, Q3UH66, Q3UIZ8, Q3ULB5, Q4JIM5, Q4KMM3, Q4V8B0, Q5R8Z4, Q5RDG7, Q5TGJ6, Q63553, Q6AYH9, Q6PDI6, Q80XI3, Q8BHL3, Q8BWQ5

Diamond homologs: A0A078CGE6, A2AQW0, A2QHV0, A2YMV6, A9RVK2, A9SY39, C4YRB7, D4A280, M9PGC5, O14305, O24527, O75914, O81472, O88643, P0CY23, P0CY24, P35465, P41892, P83741, Q01577, Q03497, Q08E52, Q0CL79, Q0D541, Q0D598, Q0D847, Q13153, Q13177, Q17850, Q21029, Q29502, Q297L2, Q2QXC6, Q2QYL8, Q2RA93, Q2RBE3, Q2ULU3, Q2V338, Q2VWQ3, Q39008

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
MAP2K6	up-regulates	PAK6	phosphorylation
MAPK14	up-regulates	PAK6	phosphorylation
PAK6	“up-regulates activity”	MDM2	phosphorylation
PAK6	“up-regulates activity”	GATA1	phosphorylation
PAK6	“down-regulates activity”	AIFM1	phosphorylation
PAK6	“up-regulates activity”	LIMK1	phosphorylation
PAK6	“up-regulates activity”	RAF1	phosphorylation
PAK6	“down-regulates quantity by destabilization”	AR	phosphorylation
PAK6	“up-regulates quantity”	SLC25A5	phosphorylation
PAK6	“down-regulates quantity”	CTNNB1	phosphorylation
miR-3191	“down-regulates quantity by destabilization”	PAK6	“post transcriptional regulation”
PAK6	“down-regulates activity”	RHOC	phosphorylation
PAK6	“up-regulates quantity”	SOX2	phosphorylation
PAK6	“up-regulates activity”	PACSIN1	phosphorylation
PAK6	“up-regulates activity”	SYNJ1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	126.0×	2e-09
Activation of BAD and translocation to mitochondria	5	119.0×	6e-08
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	105.0×	9e-08
Activation of BH3-only proteins	5	77.6×	3e-07
RHO GTPases activate PKNs	5	49.6×	2e-06
Intrinsic Pathway for Apoptosis	5	45.8×	3e-06
Apoptosis	6	31.5×	1e-06
G2/M Checkpoints	7	29.4×	3e-07

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	7	17.9×	5e-05
endocytosis	5	11.6×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

111 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

2467 predictions. Top by Δscore:

Variant	Effect	Δscore
15:40217482:A:AG	acceptor_gain	1.0000
15:40217483:A:G	acceptor_gain	1.0000
15:40217483:AATCT:A	acceptor_gain	1.0000
15:40217484:ATCT:A	acceptor_gain	1.0000
15:40217487:T:A	acceptor_gain	1.0000
15:40217663:ACCAG:A	donor_gain	1.0000
15:40217664:CCAG:C	donor_gain	1.0000
15:40217664:CCAGG:C	donor_loss	1.0000
15:40217665:CAG:C	donor_gain	1.0000
15:40217665:CAGGT:C	donor_loss	1.0000
15:40217666:AG:A	donor_gain	1.0000
15:40217666:AGG:A	donor_loss	1.0000
15:40217667:GG:G	donor_gain	1.0000
15:40217667:GGTA:G	donor_loss	1.0000
15:40217668:G:GG	donor_gain	1.0000
15:40217669:T:A	donor_loss	1.0000
15:40219316:A:G	acceptor_gain	1.0000
15:40264774:C:G	acceptor_gain	1.0000
15:40264776:TACA:T	acceptor_loss	1.0000
15:40264778:CAGG:C	acceptor_loss	1.0000
15:40264779:A:AC	acceptor_loss	1.0000
15:40264779:A:AG	acceptor_gain	1.0000
15:40264779:AG:A	acceptor_gain	1.0000
15:40264780:G:GG	acceptor_gain	1.0000
15:40264780:GG:G	acceptor_gain	1.0000
15:40264780:GGC:G	acceptor_gain	1.0000
15:40264780:GGCA:G	acceptor_gain	1.0000
15:40264780:GGCAC:G	acceptor_gain	1.0000
15:40264986:GAAG:G	donor_gain	1.0000
15:40264988:AGGT:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000019926 (15:40241520 C>T), RS1000023967 (15:40276520 C>T), RS1000118026 (15:40250372 C>A,T), RS1000127934 (15:40246554 C>G,T), RS1000323093 (15:40245886 T>C), RS1000393045 (15:40257137 C>A,T), RS1000398698 (15:40256623 G>A), RS1000399436 (15:40250025 T>C), RS1000447767 (15:40251297 C>G,T), RS1000541237 (15:40241699 G>A), RS1000596432 (15:40270043 C>T), RS1000631231 (15:40251606 T>C), RS1000854681 (15:40259879 T>C), RS1000865906 (15:40237586 A>G), RS1001120302 (15:40277971 C>T)

Disease associations

OMIM: gene MIM:608110 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001762_2	Obesity-related traits	1.000000e-06
GCST002539_24	Schizophrenia	4.000000e-09
GCST006040_2	Atopy	3.000000e-06
GCST006803_39	Schizophrenia	2.000000e-08
GCST008462_11	Plasma factor V levels in venous thrombosis (conditioned on rs6027)	2.000000e-06
GCST010007_7	Weight gain in amisulpride-treated first-episode psychosis	5.000000e-06
GCST012292_14	Schizophrenia, bipolar disorder or recurrent major depressive disorder x sex interaction	9.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004626	IGFBP-3 measurement
EFO:0005937	longitudinal BMI measurement
EFO:0004952	disease recurrence
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4311 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

13 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 114,200 (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
CHEMBL180022	NERATINIB	4	9,404
CHEMBL535	SUNITINIB	4	79,020
CHEMBL603469	LESTAURTINIB	3
CHEMBL475251	R-406	2	762
CHEMBL495727	AT-9283	2	1,376
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL574737	UCN-01	2	2,217
CHEMBL575448	BMS-754807	2	406
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
GSK690693	Inhibition	8.22	pIC50
AMG28	Inhibition	7.22	pIC50
compound 4 [PMID: 24432870]	Inhibition	6.9	pIC50
PF-3758309	Inhibition	6.74	pIC50

Binding affinities (BindingDB)

3 measured of 6 human assays (6 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 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

45 potent at pChembl≥5 of 46 total, top 40 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.40	Kd	0.4	nM	STAUROSPORINE
9.24	Kd	0.57	nM	STAUROSPORINE
8.52	Kd	3	nM	PF-03758309
8.40	Kd	4	nM	UCN-01
8.22	IC50	6	nM	GSK-690693
8.00	Kd	9.9	nM	LESTAURTINIB
7.77	IC50	17.1	nM	PF-03758309
7.72	Kd	19	nM	CHEMBL3990456
7.68	Kd	21	nM	GSK-690693
7.66	Kd	22	nM	CHEMBL4465866
7.60	Kd	25	nM	CHEMBL4576489
7.51	IC50	31	nM	STAUROSPORINE
7.51	IC50	30.7	nM	STAUROSPORINE
7.46	IC50	34.5	nM	STAUROSPORINE
7.44	IC50	36	nM	CHEMBL3128042
7.22	IC50	60	nM	CHEMBL2334586
7.22	IC50	60	nM	GSK-690693
6.96	Kd	110	nM	CHEMBL3416026
6.96	Kd	108.9	nM	CHEMBL3752910
6.83	ED50	146.2	nM	CHEMBL3752910
6.81	Kd	155	nM	GSK-690693
6.67	Kd	213	nM	AT-9283
6.51	Kd	310	nM	R-406
6.41	Kd	392.2	nM	CHEMBL5653589
6.30	Ki	500	nM	SUNITINIB
6.28	ED50	526.5	nM	CHEMBL5653589
6.12	Kd	760	nM	CHEMBL379218
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.96	Kd	1100	nM	CHEMBL1241674
5.89	Kd	1300	nM	KW-2449
5.85	Kd	1400	nM	JNJ-7706621
5.62	Kd	2400	nM	SUNITINIB
5.54	Kd	2900	nM	RUXOLITINIB
5.46	Kd	3500	nM	TAE-684
5.25	Kd	5600	nM	CHEMBL1908395
5.16	Kd	6900	nM	FEDRATINIB
5.12	Kd	7500	nM	NERATINIB
5.01	Kd	9700	nM	TOZASERTIB

PubChem BioAssay actives

74 with measured affinity, of 2165 total; 26 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	256573: Average Binding Constant for PAK6; NA=Not Active at 10 uM	kd	0.0004	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	1425101: 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	0.0030	uM
(2S,3R,4R,6R,18S)-18-hydroxy-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	1425101: 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
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	391397: Inhibition of human PAK6	ic50	0.0060	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	507660: Binding affinity to PAK6	kd	0.0099	uM
2-amino-2-cyclohexyl-N-[2-(1-methylpyrazol-4-yl)-9-oxo-3,10,11-triazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13),11-pentaen-6-yl]acetamide	1425101: 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	0.0190	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	1526219: Binding affinity to recombinant human full-length N-terminal GST-tagged PAK6 expressed in baculovirus expression system using SGKtide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0220	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	1526219: Binding affinity to recombinant human full-length N-terminal GST-tagged PAK6 expressed in baculovirus expression system using SGKtide as substrate incubated for 1 hr by TR-FRET assay	kd	0.0250	uM
1-[2-[3-(2-aminopyrimidin-4-yl)-2-(2-methoxyethylamino)benzimidazol-5-yl]ethynyl]cyclohexan-1-ol	1074642: Inhibition of PAK6 (unknown origin)	ic50	0.0360	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	1856572: Inhibition of human wild type partial length PAK6 (N298 to C681 residues) expressed in bacterial expression system by Kinomescan assay	ic50	0.0600	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148935: Binding affinity to PAK6 human incubated for 45 mins by Kinobead based pull down assay	kd	0.1089	uM
3-[[(1R,2S)-2-aminocyclohexyl]amino]-5-(1H-indol-7-ylamino)-1,2,4-triazine-6-carboxamide	1199670: Competitive binding affinity to human PAK6	kd	0.1100	uM
1-cyclopropyl-3-[5-[6-(morpholin-4-ylmethyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl]urea	1425101: 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	0.2130	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	625115: Binding constant for PAK6 kinase domain	kd	0.3100	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148935: Binding affinity to PAK6 human incubated for 45 mins by Kinobead based pull down assay	kd	0.3922	uM
Sunitinib	1453241: Inhibition of PAK6 (unknown origin)	ki	0.5000	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	625115: Binding constant for PAK6 kinase domain	kd	0.7600	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	625115: Binding constant for PAK6 kinase domain	kd	1.1000	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625115: Binding constant for PAK6 kinase domain	kd	1.3000	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435188: Binding constant for PAK6 kinase domain	kd	1.4000	uM
Ruxolitinib	625115: Binding constant for PAK6 kinase domain	kd	2.9000	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	625115: Binding constant for PAK6 kinase domain	kd	3.5000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625115: Binding constant for PAK6 kinase domain	kd	5.6000	uM
Fedratinib	625115: Binding constant for PAK6 kinase domain	kd	6.9000	uM
Neratinib	625115: Binding constant for PAK6 kinase domain	kd	7.5000	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	625115: Binding constant for PAK6 kinase domain	kd	9.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases methylation, affects cotreatment, increases expression, affects expression	6
Estradiol	decreases expression, affects binding, decreases reaction, increases reaction, affects cotreatment	3
entinostat	increases expression, affects cotreatment	2
bisphenol AF	affects binding, affects folding, increases reaction, decreases reaction	2
Benzo(a)pyrene	increases expression, affects methylation, decreases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression	2
aristolochic acid I	increases expression	1
fluorene-9-bisphenol	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects binding, affects folding, increases reaction	1
afimoxifene	decreases response to substance	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
cupric chloride	decreases expression	1
vanadyl sulfate	decreases expression	1
mercuric bromide	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects binding, decreases reaction	1
incobotulinumtoxinA	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Calcitriol	decreases expression	1
Cocaine	decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Lead	affects expression	1

ChEMBL screening assays

277 unique, capped per target: 277 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1003323	Binding	Inhibition of PAK6 at 1 uM relative to control	Novel potent BRAF inhibitors: toward 1 nM compounds through optimization of the central phenyl ring. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8S1	Ubigene HCT 116 PAK6 KO	Cancer cell line	Male
CVCL_D9M9	Ubigene HEK293 PAK6 KO	Transformed cell line	Female
CVCL_E0JQ	Ubigene HeLa PAK6 KO	Cancer cell line	Female
CVCL_TB97	HAP1 PAK6 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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