Langbahn Team – Weltmeisterschaft

PAK4

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

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

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

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

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

Regulation

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

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

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

PAK4 has been shown to interact with:

Notes

References

  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.
  11. ^ a b Callow MG, Zozulya S, Gishizky ML, Jallal B, Smeal T (May 2005). "PAK4 mediates morphological changes through the regulation of GEF-H1". Journal of Cell Science. 118 (Pt 9): 1861–72. doi:10.1242/jcs.02313. PMID 15827085.
  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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  14. ^ Kumar R, Li DQ (2016). PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. Vol. 130. pp. 137–209. doi:10.1016/bs.acr.2016.01.002. ISBN 978-0-12-804789-7. PMID 27037753. {{cite book}}: |journal= ignored (help)
  15. ^ Baskaran Y, Ng YW, Selamat W, Ling FT, Manser E (June 2012). "Group I and II mammalian PAKs have different modes of activation by Cdc42". EMBO Reports. 13 (7): 653–9. doi:10.1038/embor.2012.75. PMC 3388789. PMID 22653441.
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  19. ^ Spratley SJ, Bastea LI, Döppler H, Mizuno K, Storz P (September 2011). "Protein kinase D regulates cofilin activity through p21-activated kinase 4". The Journal of Biological Chemistry. 286 (39): 34254–61. doi:10.1074/jbc.M111.259424. PMC 3190831. PMID 21832093.
  20. ^ Park MH, Lee HS, Lee CS, You ST, Kim DJ, Park BH, Kang MJ, Heo WD, Shin EY, Schwartz MA, Kim EG (May 2013). "p21-Activated kinase 4 promotes prostate cancer progression through CREB". Oncogene. 32 (19): 2475–82. doi:10.1038/onc.2012.255. PMID 22710715. S2CID 24463782.
  21. ^ Mak GW, Chan MM, Leong VY, Lee JM, Yau TO, Ng IO, Ching YP (April 2011). "Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis". Cancer Research. 71 (8): 2949–58. doi:10.1158/0008-5472.CAN-10-4046. PMID 21385901.
  22. ^ Kim TW, Kang YK, Park ZY, Kim YH, Hong SW, Oh SJ, Sohn HA, Yang SJ, Jang YJ, Lee DC, Kim SY, Yoo HS, Kim E, Yeom YI, Park KC (March 2014). "SH3RF2 functions as an oncogene by mediating PAK4 protein stability". Carcinogenesis. 35 (3): 624–34. doi:10.1093/carcin/bgt338. PMID 24130170.
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  25. ^ Wong LE, Reynolds AB, Dissanayaka NT, Minden A (August 2010). "p120-catenin is a binding partner and substrate for Group B Pak kinases". Journal of Cellular Biochemistry. 110 (5): 1244–54. doi:10.1002/jcb.22639. PMID 20564219. S2CID 24567609.
  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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  28. ^ a b Wang C, Li Y, Zhang H, Liu F, Cheng Z, Wang D, Wang G, Xu H, Zhao Y, Cao L, Li F (June 2014). "Oncogenic PAK4 regulates Smad2/3 axis involving gastric tumorigenesis". Oncogene. 33 (26): 3473–84. doi:10.1038/onc.2013.300. PMID 23934187. S2CID 6284169.
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  35. ^ Song S, Li X, Guo J, Hao C, Feng Y, Guo B, Liu T, Zhang Q, Zhang Z, Li R, Wang J, Lin B, Li F, Zhao D, Cheng M (March 2015). "Design, synthesis and biological evaluation of 1-phenanthryl-tetrahydroisoquinoline derivatives as novel p21-activated kinase 4 (PAK4) inhibitors". Organic & Biomolecular Chemistry. 13 (12): 3803–18. doi:10.1039/c5ob00037h. PMID 25705811. S2CID 205989042.
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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.
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Quelle: https://en.wikipedia.org/wiki/PAK4