PAK4

Quality 0.50 · 1 view · Updated 2 months ago

Mammalian protein found in Homo sapiens

title: "PAK4" 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/PAK4" 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 4 is an enzyme that in humans is encoded by the PAK4 gene.

PAK4 is one of six members of the PAK family of serine/threonine kinases which are divided into group I (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7). PAK4 localizes in sub-cellular domains of the cytoplasm and nucleus. PAK4 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects directional motility, invasion, metastasis, and growth. Similar to PAK1, PAK4-signaling-dependent cellular functions also regulate both physiologic and disease processes such as cancer, as PAK4 is overexpressed and/or hyperstimulated in human cancer, at-large.

Discovery

PAK4, the founding member of Group II PAK member, was cloned and identified by Minden A. and colleagues in 1998 using a PCR-based strategy from a cDNA library prepared from Jurkett cells.

Gene and spliced variants

The group II PAKs have less coding exons compared with group I PAKs, highlights the potential structural and functional differences between two group of PAKs. The human PAK4 is about 57-kb in length with 13 exons. The PAK4 generates 12 transcripts of which 10 coding transcripts are predicted to code proteins of about 438 to 591 amino acids long, while remaining two transcripts are non-coding in nature. In contrast to human PAK4, murine PAK4 contains four transcripts - two coding for 593 amino acids long polypeptides and two are non-coding RNA transcripts.

Protein domains

The core domains of PAK4 include, a kinase domain in the C-terminal region, a p21-binding domain (PBD), and a newly defined auto-inhibitory domain (AID) or an AID-like pseudosubstrate sequence (PS) domain.

Regulation

PAK4 activity is stimulated by upstream activators and signals, including by HGF, PKD, PKA, CDK5RAP3, and SH3RF2.

In addition to other mechanisms, PAK4 functions are mediated though phosphorylation of its effector proteins, including, LIMK1-Thr508, integrin β5-Ser759/Ser762, p120-catenin-Ser288, superior cervical ganglia 10 (SCG10)-Ser50, GEF-H1-Ser810 β-catenin-Ser675, and Smad2-Ser465.

PAK4 and/or PAK4-dependent signals also modulate the expression of genomic targets, including p57Kip2.

Inhibitors

The PAK4 activity and expression has been shown to be inhibited by chemical inhibitors such as PF-3758309, LCH-7749944, glaucarubinone, KY-04031, KY-04045, 1-phenanthryl-tetrahydroisoquinoline derivatives, (-)-β-hydrastine, Inka1, GL-1196, GNE-2861, and microRNAs such as miR-145, miR-433, and miR-126.

Function

PAK proteins, a family of serine/threonine p21-activating kinases, include PAK1, PAK2, PAK3 and PAK4. PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. They serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK4 interacts specifically with the GTP-bound form of Cdc42Hs and weakly activates the JNK family of MAP kinases. PAK4 is a mediator of filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. PAK4 has been shown to be repressed at translational level by miR-24.

PAK4 regulates cellular processes by its scaffolding activity and/or by phosphorylation of effector substrates, which in-turn, set-up a cascades of biochemical events cumulating into a cellular phenotypic response. Examples of PAK4-regulated cellular processes include, dynamic reorganization of actin, and microtubule fibers, anchorage-independent growth, filopodium formation, and cell motility.

  • ITGB5, cell survival embryonic development, supports stem cell-like phenotypes, and gene expression. Modulation of PAK4 signaling has been shown to lead to significant functional implications in a number of disease conditions, exemplified by oncogenesis, cancer cell invasion and metastasis.

Interactions

PAK4 has been shown to interact with:

Notes

References

References

  1. (November 1998). "PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia". The EMBO Journal.
  2. (September 1999). "Pak to the future". Trends in Cell Biology.
  3. "Entrez Gene: PAK4 p21(CDKN1A)-activated kinase 4".
  4. (November 1998). "PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia". The EMBO Journal.
  5. (December 2003). "P21-activated kinases in human cancer". Cancer and Metastasis Reviews.
  6. (February 2012). "Nucleo-cytoplasmic shuttling of PAK4 modulates β-catenin intracellular translocation and signaling". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.
  7. (May 2005). "PAK4 mediates morphological changes through the regulation of GEF-H1". Journal of Cell Science.
  8. (January 2016). "Group II p21-activated kinases as therapeutic targets in gastrointestinal cancer". World Journal of Gastroenterology.
  9. (April 2010). "PAK as a therapeutic target in gastric cancer". Expert Opinion on Therapeutic Targets.
  10. (2016). "PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology". Advances in Cancer Research.
  11. (June 2012). "Group I and II mammalian PAKs have different modes of activation by Cdc42". EMBO Reports.
  12. (October 2012). "Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate". Proceedings of the National Academy of Sciences of the United States of America.
  13. (October 2002). "PAK4 is activated via PI3K in HGF-stimulated epithelial cells". Journal of Cell Science.
  14. (October 2013). "Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase 4". The Biochemical Journal.
  15. (September 2011). "Protein kinase D regulates cofilin activity through p21-activated kinase 4". The Journal of Biological Chemistry.
  16. (May 2013). "p21-Activated kinase 4 promotes prostate cancer progression through CREB". Oncogene.
  17. (April 2011). "Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis". Cancer Research.
  18. (March 2014). "SH3RF2 functions as an oncogene by mediating PAK4 protein stability". Carcinogenesis.
  19. (July 2008). "A PAK4-LIMK1 pathway drives prostate cancer cell migration downstream of HGF". Cellular Signalling.
  20. (July 2010). "p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration". The Journal of Biological Chemistry.
  21. (August 2010). "p120-catenin is a binding partner and substrate for Group B Pak kinases". Journal of Cellular Biochemistry.
  22. (June 2014). "PAK4 kinase-mediated SCG10 phosphorylation involved in gastric cancer metastasis". Oncogene.
  23. (May 2010). "PAK4: a pluripotent kinase that regulates prostate cancer cell adhesion". Journal of Cell Science.
  24. (June 2014). "Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis". Oncogene.
  25. (October 2013). "P21-activated kinase 4 regulates the cyclin-dependent kinase inhibitor p57(kip2) in human breast cancer". Anatomical Record.
  26. (May 2010). "Small-molecule p21-activated kinase inhibitor PF-3758309 is a potent inhibitor of oncogenic signaling and tumor growth". Proceedings of the National Academy of Sciences of the United States of America.
  27. (April 2012). "LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells". Cancer Letters.
  28. (May 2014). "Glaucarubinone and gemcitabine synergistically reduce pancreatic cancer growth via down-regulation of P21-activated kinases". Cancer Letters.
  29. (July 2014). "Discovery and the structural basis of a novel p21-activated kinase 4 inhibitor". Cancer Letters.
  30. (June 2016). "The discovery and the structural basis of an imidazo[4,5-b]pyridine-based p21-activated kinase 4 inhibitor". Bioorganic & Medicinal Chemistry Letters.
  31. (March 2015). "Design, synthesis and biological evaluation of 1-phenanthryl-tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors". Organic & Biomolecular Chemistry.
  32. (April 2016). "(-)-β-hydrastine suppresses the proliferation and invasion of human lung adenocarcinoma cells by inhibiting PAK4 kinase activity". Oncology Reports.
  33. (November 2015). "An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1". Nature Communications.
  34. (April 2016). "GL-1196 Suppresses the Proliferation and Invasion of Gastric Cancer Cells via Targeting PAK4 and Inhibiting PAK4-Mediated Signaling Pathways". International Journal of Molecular Sciences.
  35. (December 2015). "p21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells". Oncotarget.
  36. (October 2012). "MiR-145 regulates PAK4 via the MAPK pathway and exhibits an antitumor effect in human colon cells". Biochemical and Biophysical Research Communications.
  37. (January 2015). "MicroRNA-433 inhibits cell proliferation in hepatocellular carcinoma by targeting p21 activated kinase (PAK4)". Molecular and Cellular Biochemistry.
  38. (May 2015). "microRNA-126 suppresses PAK4 expression in ovarian cancer SKOV3 cells". Oncology Letters.
  39. (October 2012). "miR-24 triggers epidermal differentiation by controlling actin adhesion and cell migration". The Journal of Cell Biology.
  40. (May 2001). "Activated PAK4 regulates cell adhesion and anchorage-independent growth". Molecular and Cellular Biology.
  41. (September 2002). "P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration". The Journal of Cell Biology.
  42. (April 2001). "The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis". The Journal of Biological Chemistry.
  43. (October 2003). "PAK4 kinase is essential for embryonic viability and for proper neuronal development". Molecular and Cellular Biology.
  44. (January 2016). "p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling". Cancer Letters.
  45. (June 2009). "Pak4, a novel Gab1 binding partner, modulates cell migration and invasion by the Met receptor". Molecular and Cellular Biology.
  46. (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology.
  47. (January 2002). "PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells". Molecular and Cellular Biology.
  48. (August 2001). "Cytoskeletal changes regulated by the PAK4 serine/threonine kinase are mediated by LIM kinase 1 and cofilin". The Journal of Biological Chemistry.

::callout[type=info title="Wikipedia Source"] This article was imported from Wikipedia and is available under the Creative Commons Attribution-ShareAlike 4.0 License. Content has been adapted to SurfDoc format. Original contributors can be found on the article history page. ::