Wikipedia

PAK4

Serine/threonine-protein kinase PAK 4 is an enzyme that in humans is encoded by the PAK4 gene.[5][6][7]

PAK4
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPAK4, p21 (RAC1) activated kinase 4
External IDsOMIM: 605451; MGI: 1917834; HomoloGene: 4300; GeneCards: PAK4; OMA:PAK4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10298

70584

Ensembl

ENSG00000130669

ENSMUSG00000030602

UniProt

O96013

Q8BTW9

RefSeq (mRNA)

NM_027470

RefSeq (protein)

NP_001014831
NP_001014832
NP_001014834
NP_001014835
NP_005875

NP_081746

Location (UCSC)Chr 19: 39.13 – 39.18 MbChr 7: 28.26 – 28.3 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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).[8][9] PAK4 localizes in sub-cellular domains of the cytoplasm and nucleus.[8][10][11] PAK4 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects directional motility, invasion, metastasis, and growth.[12] 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.[13][14]

Discovery

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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.[8]

Gene and spliced variants

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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

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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) [15] or an AID-like pseudosubstrate sequence (PS) domain.[16]

Regulation

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PAK4 activity is stimulated by upstream activators and signals, including by HGF,[17] PKD,[18][19] PKA,[20] CDK5RAP3,[21] and SH3RF2.[22]

In addition to other mechanisms, PAK4 functions are mediated though phosphorylation of its effector proteins, including, LIMK1-Thr508,[23] integrin β5-Ser759/Ser762,[24] p120-catenin-Ser288,[25] superior cervical ganglia 10 (SCG10)-Ser50,[26] GEF-H1-Ser810[11][27] β-catenin-Ser675,[10] and Smad2-Ser465.[28]

PAK4 and/or PAK4-dependent signals also modulate the expression of genomic targets, including p57Kip2.[29]

Inhibitors

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The PAK4 activity and expression has been shown to be inhibited by chemical inhibitors such as PF-3758309,[30] LCH-7749944,[31] glaucarubinone,[32] KY-04031,[33] KY-04045,[34] 1-phenanthryl-tetrahydroisoquinoline derivatives,[35] (-)-β-hydrastine,[36] Inka1,[37] GL-1196,[38] GNE-2861,[39] and microRNAs such as miR-145,[40] miR-433,[41] and miR-126.[42]

Function

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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.[7] PAK4 has been shown to be repressed at translational level by miR-24.[43]

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,[23] and microtubule fibers,[26] anchorage-independent growth,[44] filopodium formation,[8] and cell motility.

  • ITGB5,[45] cell survival[46] embryonic development,[47] supports stem cell-like phenotypes,[48] and gene expression.[10] Modulation of PAK4 signaling has been shown to lead to significant functional implications in a number of disease conditions, exemplified by oncogenesis,[28] cancer cell invasion and metastasis.[26][49]

Interactions

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PAK4 has been shown to interact with:

Notes

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000130669 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000030602 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Abo A, Qu J, Cammarano MS, Dan C, Fritsch A, Baud V, Belisle B, Minden A (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. 17 (22): 6527–40. doi:10.1093/emboj/17.22.6527. PMC 1171000. PMID 9822598.
  6. ^ Bagrodia S, Cerione RA (September 1999). "Pak to the future". Trends in Cell Biology. 9 (9): 350–5. doi:10.1016/S0962-8924(99)01618-9. PMID 10461188.
  7. ^ a b "Entrez Gene: PAK4 p21(CDKN1A)-activated kinase 4".
  8. ^ a b c d Abo A, Qu J, Cammarano MS, Dan C, Fritsch A, Baud V, Belisle B, Minden A (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. 17 (22): 6527–40. doi:10.1093/emboj/17.22.6527. PMC 1171000. PMID 9822598.
  9. ^ Vadlamudi RK, Kumar R (December 2003). "P21-activated kinases in human cancer". Cancer and Metastasis Reviews. 22 (4): 385–93. doi:10.1023/a:1023729130497. PMID 12884913. S2CID 5763102.
  10. ^ a b c Li Y, Shao Y, Tong Y, Shen T, Zhang J, Li Y, Gu H, Li F (February 2012). "Nucleo-cytoplasmic shuttling of PAK4 modulates β-catenin intracellular translocation and signaling". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1823 (2): 465–75. doi:10.1016/j.bbamcr.2011.11.013. PMID 22173096.
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  12. ^ Shao YG, Ning K, Li F (January 2016). "Group II p21-activated kinases as therapeutic targets in gastrointestinal cancer". World Journal of Gastroenterology. 22 (3): 1224–35. doi:10.3748/wjg.v22.i3.1224. PMC 4716033. PMID 26811660.
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  26. ^ a b c Guo Q, Su N, Zhang J, Li X, Miao Z, Wang G, Cheng M, Xu H, Cao L, Li F (June 2014). "PAK4 kinase-mediated SCG10 phosphorylation involved in gastric cancer metastasis". Oncogene. 33 (25): 3277–87. doi:10.1038/onc.2013.296. PMID 23893240.
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  47. ^ Qu J, Li X, Novitch BG, Zheng Y, Kohn M, Xie JM, Kozinn S, Bronson R, Beg AA, Minden A (October 2003). "PAK4 kinase is essential for embryonic viability and for proper neuronal development". Molecular and Cellular Biology. 23 (20): 7122–33. doi:10.1128/mcb.23.20.7122-7133.2003. PMC 230313. PMID 14517283.
  48. ^ Tyagi N, Marimuthu S, Bhardwaj A, Deshmukh SK, Srivastava SK, Singh AP, McClellan S, Carter JE, Singh S (January 2016). "p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling". Cancer Letters. 370 (2): 260–7. doi:10.1016/j.canlet.2015.10.028. PMC 4684758. PMID 26546043.
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  50. ^ Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
  51. ^ Dan C, Nath N, Liberto M, Minden A (January 2002). "PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells". Molecular and Cellular Biology. 22 (2): 567–77. doi:10.1128/MCB.22.2.567-577.2002. PMC 139731. PMID 11756552.
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