PAK1

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Mammalian protein found in Homo sapiens

title: "PAK1" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public description: "Mammalian protein found in Homo sapiens" topic_path: "uncategorized" source: "https://en.wikipedia.org/wiki/PAK1" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Mammalian protein found in Homo sapiens ::

Serine/threonine-protein kinase PAK 1 is an enzyme that in humans is encoded by the PAK1 gene.

PAK1 is one of six members of the PAK family of serine/threonine kinases which are broadly divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7). The PAKs are evolutionarily conserved. PAK1 localizes in distinct sub-cellular domains in the cytoplasm and nucleus. PAK1 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects a wide variety of cellular processes such as directional motility, invasion, metastasis, growth, cell cycle progression, angiogenesis. PAK1-signaling dependent cellular functions regulate both physiologic and disease processes, including cancer, as PAK1 is widely overexpressed and hyperstimulated in human cancer, at-large.

Discovery

PAK1 was first discovered as an effector of the Rho GTPases in rat brain by Manser and colleagues in 1994. The human PAK1 was identified as a GTP-dependent interacting partner of Rac1 or Cdc42 in the cytosolic fraction from neutrophils, and its complementary DNA was cloned from a human placenta library by Martin and Colleagues in 1995.

Function

PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. PAK proteins, a family of serine/threonine p21-activated kinases, include PAK1, PAK2, PAK3 and PAK4. These proteins serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK1 regulates cell motility and morphology. Alternative transcripts of this gene have been found, but their full-length natures have not been determined.

Stimulation of PAK1 activity is accompanied by a series of cellular processes that are fundamental to living systems. PAK1 is a nodular signaling molecule, and operates as a converging station of a large number of signals triggered by proteins on the cell surface as well as upstream activators.

At the biochemical level, these activities are regulated by the ability of PAK1 to phosphorylate its effector interacting substrates, which sets up a cascade of biochemical events culminating in a cellular phenotypic response. PAK1 action is also influenced by its scaffolding activity. Examples of PAK1-regulated cellular processes include actin and microtubule fiber movement, critical steps during cell cycle progression, cell motility and invasion, redox and energy metabolism, cell survival, angiogenesis, DNA repair, hormone sensitivity, and gene expression. PAK1 signaling is implicated in oncogenesis, viral pathogenesis, cardiovascular dysregulation, and neurological disorders.

Gene and spliced variants

The human PAK1 gene is 153 kb long and consists of 23 exons. Six of these code the 5'-UTR and 17 exons code proteins. Alternative splicing of six exons generates 20 transcripts from 308 bp to 3.7 kb long. Only 12 of these spliced transcripts have open reading frames and are predicted to code ten proteins and two polypeptides. The remaining 8 transcripts are non-coding RNAs from 308 bp to 863 bp in length. Unlike the human PAK1, murine PAK1 gene generates five transcripts: three protein-coding from 508 bp to 3.0 kb long, and two non-coding RNA transcripts of about 900 bp.

Protein domains

The core domains of the PAK family include a kinase domain in the C-terminal region, a p21-binding domain, and an auto-inhibitory domain (AID) in group I PAKs. Group I PAKs exist in an inactive, closed homodimer conformation where the AID of one molecule binds to the kinase domain of another molecule. They are activated in both GTPase-dependent and independent manners.

Activation/inhibition

The AID domain suppresses the catalytic activity of its kinase domain. PAK1 activators relieve this auto-inhibition and initiate conformational rearrangements and autophosphorylation events leading to kinase activation.

IPA-3 (1,1′-disulfanediyldinaphthalen-2-ol) is a small molecule allosteric inhibitor of PAK1. Preactivated PAK1 is resistant to IPA-3. Inhibition in live cells supports a critical role for PAK in PDGF-stimulated ERK activation. Reversible covalent binding of IPA-3 to the PAK1 regulatory domain prevents GTPase docking and the subsequent switch to a catalytically active state.

PAK1 knockdown in prostate cancer cells is associated with reduced motility, reduced MMP9 secretion and increased TGFβ expression, which in these cases, is growth inhibitory. However, IPA-3's pharmacokinetic properties as well as undesirable redox effects in cells, due to the continuous reduction of the sulfhydryl moiety, make it unsuitable for clinical development.

Upstream activators

PAK1 activity is stimulated by a large number of upstream activators and signals, ranging from epidermal growth factor, heregulin-beta 1, Vascular endothelial growth factor, basic fibroblast growth factor, platelet-derived growth factor, estrogen, lysophosphatidic acid, phosphoinositides, Epithelial and Endothelial Tyrosine Kinase, Protein kinase B, JAK2, Extracellular Signal-Regulated Kinase, casein kinase II, Rac3, chemokine (C-X-C motif) ligand 1, breast cancer anti-estrogen resistance 3, Kaposi's sarcoma-associated herpesvirus-G protein-coupled receptor, hepatitis B virus X protein, STE20-related kinase adaptor protein α, RhoI, Klotho, N-acetylglucosaminyl transferase V, B-Raf proto-oncogene, casein kinase 2-interacting protein 1, and filamin A.

Downstream effector targets

Functions of PAK1 are regulated by its ability to phosphorylate downstream effector substrates, scaffold activity, redistribution to distinct sub-cellular cellular sub-domains, stimulation or repression of expression of its genomic targets either directly or indirectly, or by all of these mechanisms. Representative PAK1 effector substrates in cancer cells include: Stathmin-S16, Merlin-S518, Vimentin-S25-S38-S50-S65-S72, Histone H3-S10, FilaminA-S2152, Estrogen receptor-alpha-S305, signal transducer and activator of transcription 5a-S779, C-terminal binding protein 1-S158, Raf1-S338, Arpc1b-T21, DLC1-S88, phosphoglucomutase 1-T466, SMART/HDAC1-associated repressor protein-S3486-T3568, Tubulin Cofactor B-S65-S128, Snail-S246 vascular endothelial-cadherin-S665, poly(RC) binding protein 1-T60-S246, integrin-linked kinase 1-T173-S246, epithelium-specific Ets transcription factor 1-S207, ErbB3 binding protein 1-T261, nuclear receptor-interacting factor 3-S28, SRC3-delta4-T56-S659-676, beta-catenin-S675, BAD-S111, BAD-S112, S136, MEK1-S298, CRKII-S41, MORC family CW-type zinc finger 2-S739, Paxillin-S258, and Paxillin-S273.

Genomic targets

PAK1 and/or PAK1-dependent signals modulate the expression of its genomic targets, including, vascular endothelial growth factor, Cyclin D1, phosphofructokinase-muscle isoform, nuclear factor of activated T-cell, Cyclin B1, Tissue Factor and tissue factor pathway inhibitor, Metalloproteinase 9, and fibronectin.

Interactions

PAK1 has been shown to interact with:

Notes

References

References

  1. (May 1996). "Human Ste20 homologue hPAK1 links GTPases to the JNK MAP kinase pathway". Current Biology.
  2. (Apr 1998). "Detailed map of a region commonly amplified at 11q13-->q14 in human breast carcinoma". Cytogenetics and Cell Genetics.
  3. (January 1994). "A brain serine/threonine protein kinase activated by Cdc42 and Rac1". Nature.
  4. (May 1995). "A novel serine kinase activated by rac1/CDC42Hs-dependent autophosphorylation is related to PAK65 and STE20". The EMBO Journal.
  5. (July 2009). "PAK thread from amoeba to mammals". Journal of Cellular Biochemistry.
  6. (December 2003). "P21-activated kinases in human cancer". Cancer and Metastasis Reviews.
  7. (June 2006). "p21-activated kinases in cancer". Nature Reviews. Cancer.
  8. (January 2014). "PAK signalling during the development and progression of cancer". Nature Reviews. Cancer.
  9. (2016). "PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology". Advances in Cancer Research.
  10. "Entrez Gene: PAK1 p21/Cdc42/Rac1-activated kinase 1 (STE20 homolog, yeast)".
  11. (March 2010). "An emerging role for p21-activated kinases (Paks) in viral infections". Trends in Cell Biology.
  12. (December 2014). "PAK1 is a novel cardiac protective signaling molecule". Frontiers of Medicine.
  13. (April 2012). "PAK in Alzheimer disease, Huntington disease and X-linked mental retardation". Cellular Logistics.
  14. (April 2008). "An isoform-selective, small-molecule inhibitor targets the autoregulatory mechanism of p21-activated kinase". Chemistry & Biology.
  15. (February 2013). "P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor β expression and enhanced matrix metalloproteinase 9 secretion". The Journal of Biological Chemistry.
  16. (August 1996). "The adaptor protein Nck links receptor tyrosine kinases with the serine-threonine kinase Pak1". The Journal of Biological Chemistry.
  17. (October 1998). "Heregulin regulates cytoskeletal reorganization and cell migration through the p21-activated kinase-1 via phosphatidylinositol-3 kinase". The Journal of Biological Chemistry.
  18. (December 2000). "Vascular endothelial growth factor up-regulation via p21-activated kinase-1 signaling regulates heregulin-beta1-mediated angiogenesis". The Journal of Biological Chemistry.
  19. (May 2002). "Basic fibroblast growth factor-induced translocation of p21-activated kinase to the membrane is independent of phospholipase C-gamma1 in the differentiation of PC12 cells". Experimental & Molecular Medicine.
  20. (July 2001). "Platelet-derived growth factor requires epidermal growth factor receptor to activate p21-activated kinase family kinases". The Journal of Biological Chemistry.
  21. (January 2003). "Estrogen regulation of Pak1 and FKHR pathways in breast cancer cells". FEBS Letters.
  22. (April 2004). "Activation of p21-activated kinase 1 is required for lysophosphatidic acid-induced focal adhesion kinase phosphorylation and cell motility in human melanoma A2058 cells". European Journal of Biochemistry.
  23. (November 2010). "Phosphoinositides are essential coactivators for p21-activated kinase 1". Molecular Cell.
  24. (November 2003). "Akt phosphorylation of serine 21 on Pak1 modulates Nck binding and cell migration". Molecular and Cellular Biology.
  25. (October 2007). "JAK2 tyrosine kinase phosphorylates PAK1 and regulates PAK1 activity and functions". The Journal of Biological Chemistry.
  26. (October 2010). "ERK activation of p21 activated kinase-1 (Pak1) is critical for medulloblastoma cell migration". Clinical & Experimental Metastasis.
  27. (September 2013). "Protein kinase CK2 phosphorylates and activates p21-activated kinase 1". Molecular Biology of the Cell.
  28. (January 2000). "Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a p21-activated kinase-dependent pathway". Proceedings of the National Academy of Sciences of the United States of America.
  29. (February 2003). "Cell surface heparan sulfate participates in CXCL1-induced signaling". Biochemistry.
  30. (October 2003). "AND-34/BCAR3, a GDP exchange factor whose overexpression confers antiestrogen resistance, activates Rac, PAK1, and the cyclin D1 promoter". Cancer Research.
  31. (December 2003). "Activation of p21-activated kinase 1-nuclear factor kappaB signaling by Kaposi's sarcoma-associated herpes virus G protein-coupled receptor during cellular transformation". Cancer Research.
  32. (July 2012). "Hepatitis B virus X protein confers resistance of hepatoma cells to anoikis by up-regulating and activating p21-activated kinase 1". Gastroenterology.
  33. (May 2012). "STE20-related kinase adaptor protein α (STRADα) regulates cell polarity and invasion through PAK1 signaling in LKB1-null cells". The Journal of Biological Chemistry.
  34. (November 2012). "RhoJ regulates melanoma chemoresistance by suppressing pathways that sense DNA damage". Cancer Research.
  35. (2013). "Klotho endows hepatoma cells with resistance to anoikis via VEGFR2/PAK1 activation in hepatocellular carcinoma". PLOS ONE.
  36. (September 2013). "N-acetylglucosaminyltransferase V confers hepatoma cells with resistance to anoikis through EGFR/PAK1 activation". Glycobiology.
  37. (2014). "BRAF activates and physically interacts with PAK to regulate cell motility". Endocrine-Related Cancer.
  38. (August 2015). "The Role of the Pleckstrin Homology Domain-containing Protein CKIP-1 in Activation of p21-activated Kinase 1 (PAK1)". The Journal of Biological Chemistry.
  39. (September 2002). "Filamin is essential in actin cytoskeletal assembly mediated by p21-activated kinase 1". Nature Cell Biology.
  40. (January 2001). "Rac/Cdc42 and p65PAK regulate the microtubule-destabilizing protein stathmin through phosphorylation at serine 16". The Journal of Biological Chemistry.
  41. (January 2002). "p21-activated kinase links Rac/Cdc42 signaling to merlin". The Journal of Biological Chemistry.
  42. (February 2002). "Phosphorylation and reorganization of vimentin by p21-activated kinase (PAK)". Genes to Cells.
  43. (August 2002). "p21-activated kinase 1 interacts with and phosphorylates histone H3 in breast cancer cells". EMBO Reports.
  44. (October 2002). "P21-activated kinase-1 phosphorylates and transactivates estrogen receptor-alpha and promotes hyperplasia in mammary epithelium". The EMBO Journal.
  45. (May 2003). "Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands". The Journal of Cell Biology.
  46. (August 2003). "Functional inactivation of a transcriptional corepressor by a signaling kinase". Nature Structural Biology.
  47. (January 1992). "The generation of diversity and pattern in animal development". Cell.
  48. (February 2004). "p41-Arc subunit of human Arp2/3 complex is a p21-activated kinase-1-interacting substrate". EMBO Reports.
  49. (October 2004). "Regulation of phosphoglucomutase 1 phosphorylation and activity by a signaling kinase". Oncogene.
  50. (June 2005). "An essential role of Pak1 phosphorylation of SHARP in Notch signaling". Oncogene.
  51. (May 2005). "p21-activated kinase 1 regulates microtubule dynamics by phosphorylating tubulin cofactor B". Molecular and Cellular Biology.
  52. (April 2005). "Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions". Cancer Research.
  53. (November 2006). "VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin". Nature Cell Biology.
  54. (April 2007). "Signaling-dependent and coordinated regulation of transcription, splicing, and translation resides in a single coregulator, PCBP1". Proceedings of the National Academy of Sciences of the United States of America.
  55. (April 2007). "Phosphorylation-dependent regulation of nuclear localization and functions of integrin-linked kinase". Proceedings of the National Academy of Sciences of the United States of America.
  56. (July 2007). "Phosphorylation-dependent regulation of stability and transforming potential of ETS transcriptional factor ESE-1 by p21-activated kinase 1". The Journal of Biological Chemistry.
  57. (March 2008). "Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells". British Journal of Cancer.
  58. (September 2008). "Serine 28 phosphorylation of NRIF3 confers its co-activator function for estrogen receptor-alpha transactivation". Oncogene.
  59. (February 2010). "SRC-3Delta4 mediates the interaction of EGFR with FAK to promote cell migration". Molecular Cell.
  60. (February 2012). "A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells". Oncogene.
  61. (2011). "p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112". PLOS ONE.
  62. (January 2000). "p21-activated kinase 1 phosphorylates the death agonist bad and protects cells from apoptosis". Molecular and Cellular Biology.
  63. (July 2012). "PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling". Oncogene.
  64. (July 2003). "PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation". The Journal of Cell Biology.
  65. (2012). "PAK1 kinase promotes cell motility and invasiveness through CRK-II serine phosphorylation in non-small cell lung cancer cells". PLOS ONE.
  66. (December 2012). "MORC2 signaling integrates phosphorylation-dependent, ATPase-coupled chromatin remodeling during the DNA damage response". Cell Reports.
  67. (2015). "PAK1-mediated MORC2 phosphorylation promotes gastric tumorigenesis". Oncotarget.
  68. (February 2013). "HIV Nef, paxillin, and Pak1/2 regulate activation and secretion of TACE/ADAM10 proteases". Molecular Cell.
  69. (May 2006). "Paxillin phosphorylation at Ser273 localizes a GIT1-PIX-PAK complex and regulates adhesion and protrusion dynamics". The Journal of Cell Biology.
  70. (January 2004). "p21-activated kinase-1 signaling mediates cyclin D1 expression in mammary epithelial and cancer cells". The Journal of Biological Chemistry.
  71. (May 2005). "Nuclear localization and chromatin targets of p21-activated kinase 1". The Journal of Biological Chemistry.
  72. (December 2009). "Downregulation of p21-activated kinase-1 inhibits the growth of gastric cancer cells involving cyclin B1". International Journal of Cancer.
  73. (November 2012). "p21-activated kinase-1 signaling regulates transcription of tissue factor and tissue factor pathway inhibitor". The Journal of Biological Chemistry.
  74. (February 2013). "P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor β expression and enhanced matrix metalloproteinase 9 secretion". The Journal of Biological Chemistry.
  75. (January 2015). "Transcriptional regulation of fibronectin by p21-activated kinase-1 modulates pancreatic tumorigenesis". Oncogene.
  76. (April 2004). "p21-activated kinase 1 phosphorylates and regulates 14-3-3 binding to GEF-H1, a microtubule-localized Rho exchange factor". The Journal of Biological Chemistry.
  77. (February 2004). "p41-Arc subunit of human Arp2/3 complex is a p21-activated kinase-1-interacting substrate". EMBO Reports.
  78. (August 2001). "Etk/Bmx tyrosine kinase activates Pak1 and regulates tumorigenicity of breast cancer cells". The Journal of Biological Chemistry.
  79. (February 2002). "Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1". The Journal of Biological Chemistry.
  80. (December 2001). "Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology". The Journal of Biological Chemistry.
  81. (June 2004). "Dynein light chain 1, a p21-activated kinase 1-interacting substrate, promotes cancerous phenotypes". Cancer Cell.
  82. (September 1999). "Activation of LIM-kinase by Pak1 couples Rac/Cdc42 GTPase signalling to actin cytoskeletal dynamics". Nature Cell Biology.
  83. (February 2001). "A PAK1-PIX-PKL complex is activated by the T-cell receptor independent of Nck, Slp-76 and LAT". The EMBO Journal.
  84. (February 1999). "Identification of Grb4/Nckbeta, a src homology 2 and 3 domain-containing adapter protein having similar binding and biological properties to Nck". The Journal of Biological Chemistry.
  85. (October 1996). "Interaction of the Nck adapter protein with p21-activated kinase (PAK1)". The Journal of Biological Chemistry.
  86. (May 2001). "Regulation of the p21-activated kinase (PAK) by a human Gbeta -like WD-repeat protein, hPIP1". Proceedings of the National Academy of Sciences of the United States of America.
  87. (July 2003). "RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo". Nature.
  88. (March 2003). "ArhGAP15, a novel human RacGAP protein with GTPase binding property". FEBS Letters.
  89. (April 1998). "Interaction of Rac1 with GTPase-activating proteins and putative effectors. A comparison with Cdc42 and RhoA". The Journal of Biological Chemistry.

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