PAK1 (p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast))

2007-12-01   Dina Stepanova , Jonathan Chernoff 

Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA

Identity

HGNC
LOCATION
11q13.5
LOCUSID
ALIAS
IDDMSSD,PAKalpha,alpha-PAK,p65-PAK
FUSION GENES

DNA/RNA

Atlas Image
The alignment of PAK1 mRNA to its genomic sequence.

Description

The PAK1 gene contains 14 exons. The sizes of the exons 1-14 are 189, 100, 129, 147, 37, 119, 174, 63, 48, 112, 117, 99, 196, 137, and 86 bps. Exon 2 contains the translation initation ATG, and a few additional codons. Exon 13 contains the stop codon. Other features of the PAK1 gene, such as promoters or enhancer elements, have not been described.

Transcription

PAK1 expression is particularly high in the brain. Other tissues which have reasonably high levels of PAK1 expression include spleen and skeletal muscle. The mRNA size is 1945 bps.

Proteins

Atlas Image

Description

PAK1 is a highly conserved serine/threonine protein kinase of 545 amino acids and is a member of the PAK group of the STE20 family of serine/threonine protein kinases. Pak1 is active in a monomeric form; the non-active form is an autoinhibited homodimer. Pak1 contains a regulatory N-terminal regulatory domain and C-terminal catalytic domain The regulatory domain consists of a p21 GTPase-binding domain (PBD), an inhibitory domain (PID); five SH3-domains; and one non-classical SH3-binding site for the PIX family of proteins (PXP). Pak1 binds to activated forms of the GTPases Cdc42 and Rac. Pak1 homodimerizes through a motif adjacent to the p21-binding domain, and is autoinhibited. Upon binding to Cdc42 or Rac, Pak1 is activated and autophosphorylates. Pak1 has dozens of substrates, activating cytoskeletal and transcription pathways that enhance cell motility, proliferation, and survival.

Expression

PAK1 is highly expressed in epithelium of tongue and larynx and in thyroid gland, expression also found in central nervous system (brain).

Localisation

Under basal conditions, Pak1 localizes to the cytosol. Upon growth factor stimulation, Pak1 is recruited to the plasma membrane as well as the nucleus.

Function

Cell survival and proliferation

Homology

Similar to STE20 in budding yeast and PAK1 in fission yeast. Human PAK1 complements both these yeast genes.

Mutations

Note

No mutations in the PAK1 gene have been reported

Implicated in

Entity name
Cancers
Disease
There is emerging evidence that the Pak family may play a key role in several human malignancies, including breast, ovarian, head and neck, colon, thyroid, and renal cancer. In human breast cancer, the expression level of Pak1 correlates with the tumor grade, with higher expression in less differentiated ductal carcinomas of the breast (grade III tumors) than in grade II and grade I tumors. Pak1 overexpression is also associated with tamoxifen resistance in breast cancer. In human tumors, Pak1 is not itself activated by mutation: rather, Pak1 is overexpressed by unknown mechanisms. Pak1 may also play a role in transformation by Kaposis sarcoma-associated herpes virus, which induces Kaposis sarcoma and primary effusion lymphomas.
Prognosis
Recently, it has been shown that the level of phosphorylated (activated) Pak1 Level in the cytoplasm correlates with shorter survival time in patients with glioblastoma. As noted above, Pak1 expression may also correlate with tamoxifen resistance in breast cancer.

Bibliography

Pubmed IDLast YearTitleAuthors
104611881999Pak to the future.Bagrodia S et al
126767962003Biology of the p21-activated kinases.Bokoch GM et al
113166112001The Ste20 group kinases as regulators of MAP kinase cascades.Dan I et al
153316592004The genetics of Pak.Hofmann C et al
119505872002p21-activated kinases: three more join the Pak.Jaffer ZM et al
167239922006p21-activated kinases in cancer.Kumar R et al
81077741994A brain serine/threonine protein kinase activated by Cdc42 and Rac1.Manser E et al
177089351997Emerging from the Pak: the p21-activated protein kinase family.Sells MA et al

Other Information

Locus ID:

NCBI: 5058
MIM: 602590
HGNC: 8590
Ensembl: ENSG00000149269

Variants:

dbSNP: 5058
ClinVar: 5058
TCGA: ENSG00000149269
COSMIC: PAK1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000149269ENST00000278568Q13153
ENSG00000149269ENST00000356341Q13153
ENSG00000149269ENST00000356341A0A024R5P0
ENSG00000149269ENST00000524847E9PQW5
ENSG00000149269ENST00000526968E9PJF8
ENSG00000149269ENST00000527457H0YCM0
ENSG00000149269ENST00000527535H0YF55
ENSG00000149269ENST00000528203E9PM17
ENSG00000149269ENST00000528592E9PMP2
ENSG00000149269ENST00000528633E9PRP6
ENSG00000149269ENST00000529248E9PKH9
ENSG00000149269ENST00000530617B3KNX7
ENSG00000149269ENST00000533285H0YCG5

Expression (GTEx)

0
50
100
150
200

Pathways

PathwaySourceExternal ID
MAPK signaling pathwayKEGGko04010
ErbB signaling pathwayKEGGko04012
Axon guidanceKEGGko04360
Focal adhesionKEGGko04510
Natural killer cell mediated cytotoxicityKEGGko04650
T cell receptor signaling pathwayKEGGko04660
Regulation of actin cytoskeletonKEGGko04810
Epithelial cell signaling in Helicobacter pylori infectionKEGGko05120
Renal cell carcinomaKEGGko05211
MAPK signaling pathwayKEGGhsa04010
ErbB signaling pathwayKEGGhsa04012
Axon guidanceKEGGhsa04360
Focal adhesionKEGGhsa04510
Natural killer cell mediated cytotoxicityKEGGhsa04650
T cell receptor signaling pathwayKEGGhsa04660
Regulation of actin cytoskeletonKEGGhsa04810
Epithelial cell signaling in Helicobacter pylori infectionKEGGhsa05120
Renal cell carcinomaKEGGhsa05211
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Ras signaling pathwayKEGGhsa04014
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
TCR signalingREACTOMER-HSA-202403
Generation of second messenger moleculesREACTOMER-HSA-202433
Costimulation by the CD28 familyREACTOMER-HSA-388841
CD28 co-stimulationREACTOMER-HSA-389356
CD28 dependent Vav1 pathwayREACTOMER-HSA-389359
Innate Immune SystemREACTOMER-HSA-168249
Fcgamma receptor (FCGR) dependent phagocytosisREACTOMER-HSA-2029480
Regulation of actin dynamics for phagocytic cup formationREACTOMER-HSA-2029482
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
C-type lectin receptors (CLRs)REACTOMER-HSA-5621481
CD209 (DC-SIGN) signalingREACTOMER-HSA-5621575
Signal TransductionREACTOMER-HSA-162582
Signaling by VEGFREACTOMER-HSA-194138
VEGFA-VEGFR2 PathwayREACTOMER-HSA-4420097
VEGFR2 mediated vascular permeabilityREACTOMER-HSA-5218920
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK6/MAPK4 signalingREACTOMER-HSA-5687128
Signaling by Rho GTPasesREACTOMER-HSA-194315
RHO GTPase EffectorsREACTOMER-HSA-195258
RHO GTPases activate PAKsREACTOMER-HSA-5627123
Cell-Cell communicationREACTOMER-HSA-1500931
DSCAM interactionsREACTOMER-HSA-376172
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Semaphorin interactionsREACTOMER-HSA-373755
Sema3A PAK dependent Axon repulsionREACTOMER-HSA-399954
Signaling by Robo receptorREACTOMER-HSA-376176
Activation of RacREACTOMER-HSA-428540
L1CAM interactionsREACTOMER-HSA-373760
Signal transduction by L1REACTOMER-HSA-445144
EPH-Ephrin signalingREACTOMER-HSA-2682334
EPHB-mediated forward signalingREACTOMER-HSA-3928662
Ephrin signalingREACTOMER-HSA-3928664
Hippo signaling pathway -multiple speciesKEGGko04392
Hippo signaling pathway -multiple speciesKEGGhsa04392

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
128879232003Directional sensing requires G beta gamma-mediated PAK1 and PIX alpha-dependent activation of Cdc42.143
121984932002Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1.118
191654202009Pak protein kinases and their role in cancer.113
189228902008MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions.112
158338482005Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions.102
152255532004Phosphorylation of RhoGDI by Pak1 mediates dissociation of Rac GTPase.90
179811342007Cofilin activity downstream of Pak1 regulates cell protrusion efficiency by organizing lamellipodium and lamella actin networks.86
118045872002Pak1 kinase homodimers are autoinhibited in trans and dissociated upon activation by Cdc42 and Rac1.85
183544942008The closure of Pak1-dependent macropinosomes requires the phosphorylation of CtBP1/BARS.82
167051212006Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients.75

Citation

Dina Stepanova ; Jonathan Chernoff

PAK1 (p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast))

Atlas Genet Cytogenet Oncol Haematol. 2007-12-01

Online version: http://atlasgeneticsoncology.org/gene/41633/pak1