PAK1 — p21 (RAC1) activated kinase 1

50 sources retrieved · Most recent: April 2026 · Index updated 3 months ago

573PubMed Papers

#418 · top 2% of 19K genes

21Diseases

top 8%

0Drugs

25Pathogenic Variants

top 36%

OMIM Disease GeneKinaseHighly StudiedExperimental GO EvidenceSwiss-Prot Reviewed

protein kinase activitynegative regulation of cell proliferation involved in contact inhibitionpositive regulation of stress fiber assemblyhepatocyte growth factor receptor signaling pathwayintellectual developmental disorder with macrocephaly, seizures, and speech delayNeurodevelopmental disordergenetic disorderMyoclonus

AI Summary

PAK1 (p21-activated kinase 1) is a serine/threonine protein kinase that functions as a critical hub in intracellular signaling downstream of integrins and receptor tyrosine kinases 1 2. Activated by CDC42 and RAC1 GTPases 3 4, PAK1 regulates cytoskeleton dynamics, cell adhesion, migration, and proliferation through phosphorylation of substrates including MAP2K1, RAF1, and cofilin 5 6. PAK1 also promotes autophagy by phosphorylating ATG5, a process enhanced by hypoxia-induced acetylation 7. PAK1 dysregulation is implicated in multiple cancers and neurological disorders. In glioblastoma, elevated PAK1 promotes autophagy and tumor growth; PAK1 inhibition with FRAX597 blocks these processes 7. PAK1 overexpression in bladder cancer correlates with tumor size, histological grade, and metastasis; PAK1 knockdown reduces proliferation and invasion 8. In prostate cancer, PAK1 drives androgen receptor signaling inhibitor cross-resistance through the PAK1/RELA/hnRNPA1/AR-V7 axis 9. Melanoma therapy resistance involves PAK1-mediated evasion of cell death and immunosuppression 10. In Down syndrome, elevated DSCAM/PAK1 pathway activity impairs neurogenesis; pathway suppression rescues cortical organoid development 11. PAK1 represents a tractable therapeutic target across multiple disease contexts 12 13.

Sources cited

PAK1 also promotes autophagy by phosphorylating ATG5, a process enhanced by hypoxia-induced acetylation .

PMID: 32186433

PAK1 overexpression in bladder cancer correlates with tumor size, histological grade, and metastasis; PAK1 knockdown reduces proliferation and invasion .

PMID: 25412958

In prostate cancer, PAK1 drives androgen receptor signaling inhibitor cross-resistance through the PAK1/RELA/hnRNPA1/AR-V7 axis .

PMID: 38364963

Melanoma therapy resistance involves PAK1-mediated evasion of cell death and immunosuppression .

PMID: 37830586

In Down syndrome, elevated DSCAM/PAK1 pathway activity impairs neurogenesis; pathway suppression rescues cortical organoid development .

PMID: 33945512

Disease Associations21

intellectual developmental disorder with macrocephaly, seizures, and speech delayOpen Targets

0.71Strong

Neurodevelopmental disorderOpen Targets

0.48Moderate

genetic disorderOpen Targets

0.34Weak

MyoclonusOpen Targets

0.25Weak

drug allergyOpen Targets

0.25Weak

multinodular goiterOpen Targets

0.22Weak

joint diseaseOpen Targets

0.22Weak

cutaneous melanomaOpen Targets

0.19Weak

neurodegenerative diseaseOpen Targets

0.17Weak

schizophreniaOpen Targets

0.13Weak

neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotoniaOpen Targets

0.12Weak

neoplasmOpen Targets

0.11Weak

breast cancerOpen Targets

0.11Weak

non-small cell lung carcinomaOpen Targets

0.11Weak

hepatocellular carcinomaOpen Targets

0.10Weak

colorectal carcinomaOpen Targets

0.10Weak

glioblastoma multiformeOpen Targets

0.10Weak

gastric cancerOpen Targets

0.10Suggestive

cancerOpen Targets

0.10Suggestive

ovarian cancerOpen Targets

0.09Suggestive

Intellectual developmental disorder with macrocephaly, seizures, and speech delayUniProt

Pathogenic Variants25

NM_002576.5(PAK1):c.362C>T (p.Pro121Leu)Pathogenic

PAK1-related neurodevelopmental disorders|not provided|PAK1-related disorder|Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★★☆☆2024→ Residue 121

NM_002576.5(PAK1):c.1409T>G (p.Leu470Arg)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★★☆☆2023→ Residue 470

NM_002576.5(PAK1):c.1427T>C (p.Ile476Thr)Pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay|See cases|not provided

★★☆☆2022→ Residue 476

NM_002576.5(PAK1):c.361C>T (p.Pro121Ser)Pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay|not provided

★★☆☆2022→ Residue 121

NM_002576.5(PAK1):c.428T>C (p.Met143Thr)Likely pathogenic

not provided|Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★★☆☆2021→ Residue 143

NM_002576.5(PAK1):c.1115A>C (p.Glu372Ala)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★☆☆☆2025→ Residue 372

NM_002576.5(PAK1):c.209_212del (p.Lys70fs)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★☆☆☆2024→ Residue 70

NM_002576.5(PAK1):c.427A>G (p.Met143Val)Likely pathogenic

PAK1-related disorder|not provided

★☆☆☆2023→ Residue 143

NM_002576.5(PAK1):c.1261C>T (p.Arg421Trp)Likely pathogenic

Inborn genetic diseases

★☆☆☆2023→ Residue 421

NM_002576.5(PAK1):c.391T>A (p.Tyr131Asn)Pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★☆☆☆2022→ Residue 131

NM_002576.5(PAK1):c.424T>C (p.Tyr142His)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★☆☆☆2022→ Residue 142

NM_002576.5(PAK1):c.1409T>A (p.Leu470Gln)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★☆☆☆2022→ Residue 470

NM_002576.5(PAK1):c.1420T>C (p.Tyr474His)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★☆☆☆2021→ Residue 474

NM_002576.5(PAK1):c.428T>A (p.Met143Lys)Likely pathogenic

not provided

★☆☆☆2020→ Residue 143

NM_002576.5(PAK1):c.328T>A (p.Ser110Thr)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★☆☆☆2019→ Residue 110

NM_002576.5(PAK1):c.397T>C (p.Ser133Pro)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay|not provided

★☆☆☆2019→ Residue 133

NM_002576.5(PAK1):c.392A>G (p.Tyr131Cys)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★☆☆☆2019→ Residue 131

NM_002576.5(PAK1):c.1286A>G (p.Tyr429Cys)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay|not provided

★☆☆☆2019→ Residue 429

NM_002576.5(PAK1):c.850G>A (p.Val284Met)Likely pathogenic

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

★☆☆☆→ Residue 284

NM_002576.5(PAK1):c.262G>A (p.Gly88Ser)Likely pathogenic

PAK1-related disorder

☆☆☆☆2023→ Residue 88

Tissue Expression6 tissues

Brain

100%

Bone Marrow

42%

Ovary

22%

Lung

15%

Liver

Heart

Gene Interaction Network6 neighbors

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Structure37 PDB hits

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PDB3FXZ · 1.64 Å · X-ray

View on RCSB

ConstraintgnomAD v4.1

LOEUFⓘ

0.70LoF Tolerant

pLIⓘ

0.06Tolerant

Observed/Expected LoF0.46 [0.31–0.70]

Rankings3 dim

Where PAK1 stands among ~20K protein-coding genes

#418of 20,598
Most Researched573 · top 5%
#1,973of 5,509
Most Pathogenic Variants25
#5,380of 17,882
Most Constrained (LOEUF)0.70