PAK4

Last updated
PAK4
Protein PAK4 PDB 2bva.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PAK4 , p21 (RAC1) activated kinase 4
External IDs OMIM: 605451 MGI: 1917834 HomoloGene: 4300 GeneCards: PAK4
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 Mb Chr 7: 28.26 – 28.3 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/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 MT1-MMP [29] and p57Kip2. [30]

Inhibitors

The PAK4 activity and expression has been shown to be inhibited by chemical inhibitors such as PF-3758309, [31] LCH-7749944, [32] glaucarubinone, [33] KY-04031, [34] KY-04045, [35] 1-phenanthryl-tetrahydroisoquinoline derivatives, [36] (-)-β-hydrastine, [37] Inka1, [38] GL-1196, [39] GNE-2861, [40] and microRNAs such as miR-145, [41] miR-433, [42] and miR-126. [43]

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. [44]

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, [45] filopodium formation, [8] and cell motility</ref>

Interactions

PAK4 has been shown to interact with:

Notes

Related Research Articles

p21

p21Cip1, also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated with inhibition of CDK2. p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans.

<span class="mw-page-title-main">STAT3</span> Protein-coding gene in the species Homo sapiens

Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the STAT3 gene. It is a member of the STAT protein family.

<span class="mw-page-title-main">ASK1</span> Protein-coding gene in the species Homo sapiens

Apoptosis signal-regulating kinase 1 (ASK1) also known as mitogen-activated protein kinase 5 (MAP3K5) is a member of MAP kinase family and as such a part of mitogen-activated protein kinase pathway. It activates c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinases in a Raf-independent fashion in response to an array of stresses such as oxidative stress, endoplasmic reticulum stress and calcium influx. ASK1 has been found to be involved in cancer, diabetes, rheumatoid arthritis, cardiovascular and neurodegenerative diseases.

<span class="mw-page-title-main">CDC42</span> Protein-coding gene in the species Homo sapiens

Cell division control protein 42 homolog is a protein that in humans is encoded by the CDC42 gene. Cdc42 is involved in regulation of the cell cycle. It was originally identified in S. cerevisiae (yeast) as a mediator of cell division, and is now known to influence a variety of signaling events and cellular processes in a variety of organisms from yeast to mammals.

<span class="mw-page-title-main">Cyclin D1</span> Protein found in humans

Cyclin D1 is a protein that in humans is encoded by the CCND1 gene.

<span class="mw-page-title-main">MAPK14</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase 14, also called p38-α, is an enzyme that in humans is encoded by the MAPK14 gene.

<span class="mw-page-title-main">PAK1</span> Mammalian protein found in Homo sapiens

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

<span class="mw-page-title-main">CHEK1</span> Protein-coding gene in humans

Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle.

<span class="mw-page-title-main">MAP3K7</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase 7 (MAP3K7), also known as TAK1, is an enzyme that in humans is encoded by the MAP3K7 gene.

<span class="mw-page-title-main">PAK2</span> Mammalian protein found in Homo sapiens

Serine/threonine-protein kinase PAK 2 is an enzyme that in humans is encoded by the PAK2 gene.

<span class="mw-page-title-main">DNA damage-inducible transcript 3</span> Human protein and coding gene

DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the DDIT3 gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding transcription factors. The protein functions as a dominant-negative inhibitor by forming heterodimers with other C/EBP members, preventing their DNA binding activity. The protein is implicated in adipogenesis and erythropoiesis and has an important role in the cell's stress response.

<span class="mw-page-title-main">PIM1</span> Protein-coding gene in the species Homo sapiens

Proto-oncogene serine/threonine-protein kinase Pim-1 is an enzyme that in humans is encoded by the PIM1 gene.

<span class="mw-page-title-main">PAK3</span> Mammalian protein found in Homo sapiens

PAK3 is one of three members of Group I PAK family of evolutionary conserved serine/threonine kinases. PAK3 is preferentially expressed in neuronal cells and involved in synapse formation and plasticity and mental retardation.

<span class="mw-page-title-main">GADD45G</span> Protein-coding gene in the species Homo sapiens

Growth arrest and DNA-damage-inducible protein GADD45 gamma is a protein that in humans is encoded by the GADD45G gene on chromosome 9. GADD45G is also known as CR6, DDIT2, GRP17, OIG37, and GADD45gamma. GADD45G is involved in several different processes, including sexual development, human-specific brain development, tumor suppression, and the cellular stress response. GADD45G interacts with several other proteins that are involved in DNA repair, cell cycle control, apoptosis, and senescence. Low expression of GADD45G has been associated with many types of cancer.

<span class="mw-page-title-main">MAP4K4</span> Protein-coding gene in the species Homo sapiens

Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) – also known as hepatocyte progenitor kinase-like/germinal center kinase-like kinase (HGK) and Nck-interacting kinase (NIK) – is an enzyme, specifically a serine/threonine (S/T) kinase encoded by the MAP4K4 gene in humans.

<span class="mw-page-title-main">PAK5</span>

Serine/threonine-protein kinase PAK 5 is an enzyme that in humans is encoded by the PAK5 gene.

<span class="mw-page-title-main">PAK6</span>

Serine/threonine-protein kinase PAK 6 is an enzyme that in humans is encoded by the PAK6 gene.

<span class="mw-page-title-main">Hippo signaling pathway</span> Signaling pathway that controls organ size

The Hippo signaling pathway, also known as the Salvador-Warts-Hippo (SWH) pathway, is a signaling pathway that controls organ size in animals through the regulation of cell proliferation and apoptosis. The pathway takes its name from one of its key signaling components—the protein kinase Hippo (Hpo). Mutations in this gene lead to tissue overgrowth, or a "hippopotamus"-like phenotype.

<span class="mw-page-title-main">Rho-associated protein kinase</span>

Rho-associated protein kinase (ROCK) is a kinase belonging to the AGC family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton.

<span class="mw-page-title-main">Autophosphorylation</span>

Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine or tyrosine residues within protein kinases, normally to regulate the catalytic activity. Autophosphorylation may occur when a kinases' own active site catalyzes the phosphorylation reaction, or when another kinase of the same type provides the active site that carries out the chemistry. The latter often occurs when kinase molecules dimerize. In general, the phosphate groups introduced are gamma phosphates from nucleoside triphosphates, most commonly ATP.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000130669 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 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. 1 2 "Entrez Gene: PAK4 p21(CDKN1A)-activated kinase 4".
  8. 1 2 3 4 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. 1 2 3 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. 1 2 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.
  13. ↑ Li X, Liu F, Li F (April 2010). "PAK as a therapeutic target in gastric cancer". Expert Opinion on Therapeutic Targets. 14 (4): 419–33. doi:10.1517/14728221003642019. PMID   20146633. S2CID   29910668.
  14. ↑ Kumar R, Li DQ (2016). PAKs in Human Cancer Progression: From Inception to Cancer Therapeutic to Future Oncobiology. pp. 137–209. doi:10.1016/bs.acr.2016.01.002. ISBN   9780128047897. 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.
  16. ↑ Ha BH, Davis MJ, Chen C, Lou HJ, Gao J, Zhang R, Krauthammer M, Halaban R, Schlessinger J, Turk BE, Boggon TJ (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. 109 (40): 16107–12. doi: 10.1073/pnas.1214447109 . PMC   3479536 . PMID   22988085.
  17. ↑ Wells CM, Abo A, Ridley AJ (October 2002). "PAK4 is activated via PI3K in HGF-stimulated epithelial cells". Journal of Cell Science. 115 (Pt 20): 3947–56. doi: 10.1242/jcs.00080 . PMID   12244132.
  18. ↑ Bastea LI, Döppler H, Pearce SE, Durand N, Spratley SJ, Storz P (October 2013). "Protein kinase D-mediated phosphorylation at Ser99 regulates localization of p21-activated kinase 4". The Biochemical Journal. 455 (2): 251–60. doi:10.1042/BJ20130281. PMC   3880571 . PMID   23841590.
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  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.
  23. 1 2 Ahmed T, Shea K, Masters JR, Jones GE, Wells CM (July 2008). "A PAK4-LIMK1 pathway drives prostate cancer cell migration downstream of HGF". Cellular Signalling. 20 (7): 1320–8. doi:10.1016/j.cellsig.2008.02.021. PMID   18424072.
  24. ↑ Li Z, Zhang H, Lundin L, Thullberg M, Liu Y, Wang Y, Claesson-Welsh L, Strömblad S (July 2010). "p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration". The Journal of Biological Chemistry. 285 (31): 23699–710. doi: 10.1074/jbc.M110.123497 . PMC   2911335 . PMID   20507994.
  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.
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  32. ↑ Zhang J, Wang J, Guo Q, Wang Y, Zhou Y, Peng H, Cheng M, Zhao D, Li F (April 2012). "LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells". Cancer Letters. 317 (1): 24–32. doi:10.1016/j.canlet.2011.11.007. PMID   22085492.
  33. ↑ Yeo D, Huynh N, Beutler JA, Christophi C, Shulkes A, Baldwin GS, Nikfarjam M, He H (May 2014). "Glaucarubinone and gemcitabine synergistically reduce pancreatic cancer growth via down-regulation of P21-activated kinases". Cancer Letters. 346 (2): 264–72. doi:10.1016/j.canlet.2014.01.001. hdl: 11343/43950 . PMC   7681251 . PMID   24491405.
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  35. ↑ Park JK, Kim S, Han YJ, Kim SH, Kang NS, Lee H, Park S (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. 26 (11): 2580–3. doi:10.1016/j.bmcl.2016.04.037. PMID   27117431.
  36. ↑ 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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  38. ↑ Baskaran Y, Ang KC, Anekal PV, Chan WL, Grimes JM, Manser E, Robinson RC (November 2015). "An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1". Nature Communications. 6: 8681. doi:10.1038/ncomms9681. PMC   4674680 . PMID   26607847.
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  40. ↑ Zhuang T, Zhu J, Li Z, Lorent J, Zhao C, Dahlman-Wright K, Strömblad S (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. 6 (41): 43853–68. doi:10.18632/oncotarget.6081. PMC   4791272 . PMID   26554417.
  41. ↑ Wang Z, Zhang X, Yang Z, Du H, Wu Z, Gong J, Yan J, Zheng Q (October 2012). "MiR-145 regulates PAK4 via the MAPK pathway and exhibits an antitumor effect in human colon cells". Biochemical and Biophysical Research Communications. 427 (3): 444–9. doi:10.1016/j.bbrc.2012.06.123. PMID   22766504.
  42. ↑ Xue J, Chen LZ, Li ZZ, Hu YY, Yan SP, Liu LY (January 2015). "MicroRNA-433 inhibits cell proliferation in hepatocellular carcinoma by targeting p21 activated kinase (PAK4)". Molecular and Cellular Biochemistry. 399 (1–2): 77–86. doi:10.1007/s11010-014-2234-9. PMID   25410752. S2CID   17307710.
  43. ↑ Luo P, Fei J, Zhou J, Zhang W (May 2015). "microRNA-126 suppresses PAK4 expression in ovarian cancer SKOV3 cells". Oncology Letters. 9 (5): 2225–2229. doi:10.3892/ol.2015.3012. PMC   4467333 . PMID   26137045.
  44. ↑ Amelio I, Lena AM, Viticchiè G, Shalom-Feuerstein R, Terrinoni A, Dinsdale D, Russo G, Fortunato C, Bonanno E, Spagnoli LG, Aberdam D, Knight RA, Candi E, Melino G (October 2012). "miR-24 triggers epidermal differentiation by controlling actin adhesion and cell migration". The Journal of Cell Biology. 199 (2): 347–63. doi:10.1083/jcb.201203134. PMC   3471232 . PMID   23071155.
  45. ↑ Qu J, Cammarano MS, Shi Q, Ha KC, de Lanerolle P, Minden A (May 2001). "Activated PAK4 regulates cell adhesion and anchorage-independent growth". Molecular and Cellular Biology. 21 (10): 3523–33. doi:10.1128/MCB.21.10.3523-3533.2001. PMC   100274 . PMID   11313478.
  46. 1 2 Zhang H, Li Z, Viklund EK, Strömblad S (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. 158 (7): 1287–97. doi:10.1083/jcb.200207008. PMC   2173231 . PMID   12356872.
  47. ↑ Gnesutta N, Qu J, Minden A (April 2001). "The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis" (PDF). The Journal of Biological Chemistry. 276 (17): 14414–9. doi: 10.1074/jbc.M011046200 . PMID   11278822. S2CID   23204523.
  48. ↑ 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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