PAK4

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PAK4
Protein PAK4 PDB 2bva.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases PAK4
External IDs MGI: 1917834 HomoloGene: 4300 GeneCards: PAK4
RNA expression pattern
PBB GE PAK4 203154 s at fs.png

PBB GE PAK4 33814 at fs.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_027470

RefSeq (protein)

NP_001014831
NP_001014832
NP_001014834
NP_001014835
NP_005875

NP_081746.1
NP_081746

Location (UCSC) Chr 19: 39.13 – 39.18 Mb Chr 7: 28.56 – 28.6 Mb
PubMed search [1] [2]
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.[3][4][5]

PAK4 is one of six members of the PAK family of serine/threonine kinases which are divided into group II (PAK1, PAK2 and PAK3) and group II (PAK4, PAK6 and PAK5/7).[6][7] PAK4 localizes in sub-cellular domains of the cytoplasm and nucleus.[6][8][9] PAK4 regulates cytoskeleton remodeling, phenotypic signaling and gene expression, and affects directional motility, invasion, metastasis, and growth.[10] 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.[11][12]

Discovery[edit]

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.[6]

Gene and spliced variants[edit]

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[edit]

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) [13] or an AID-like pseudosubstrate sequence (PS) domain.[14]

Regulation[edit]

PAK4 activity is stimulated by upstream activators and signals, including by HGF,[15] PKD,[16][17] PKA,[18] CDK5RAP3,[19] and SH3RF2.[20]

In addition to other mechanisms, PAK4 functions are mediated though phosphorylation of its effector proteins, including, LIMK1-Thr508,[21] integrin β5-Ser759/Ser762,[22] p120-catenin-Ser288,[23] superior cervical ganglia 10 (SCG10)-Ser50,[24] GEF-H1-Ser810[9][25] β-catenin-Ser675,[8] and Smad2-Ser465.[26]

PAK4 and/or PAK4-dependent signals also modulate the expression of genomic targets, including MT1-MMP[27] and p57Kip2.[28]

Inhibitors[edit]

The PAK4 activity and expression has been shown to be inhibited by chemical inhibitors such as PF-3758309,[29] LCH-7749944,[30] glaucarubinone,[31] KY-04031,[32] KY-04045,[33] 1-phenanthryl-tetrahydroisoquinoline derivatives,[34] (-)-β-hydrastine,[35] Inka1,[36] GL-1196,[37] GNE-2861,[38] and microRNAs such as miR-145,[39] miR-433,[40] and miR-126.[41]

Function[edit]

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.[5] PAK4 has been shown to be repressed at translational level by miR-24.[42]

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,[21] and microtubule fibers,[24] anchorage-independent growth,[43] filopodium formation,[6] and cell motility, cell survival[44] embryonic development,[45] supports stem cell-like phenotypes,[46] and gene expression.[8] Modulation of PAK4 signaling has been shown to lead to significant functional implications in a number of disease conditions, exemplified by oncogenesis,[26] cancer cell invasion and metastasis.[24][47]

Interactions[edit]

PAK4 has been shown to interact with:

References[edit]

  1. ^ "Human PubMed Reference:". 
  2. ^ "Mouse PubMed Reference:". 
  3. ^ 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 1171000Freely accessible. PMID 9822598. 
  4. ^ 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. 
  5. ^ a b "Entrez Gene: PAK4 p21(CDKN1A)-activated kinase 4". 
  6. ^ 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. PMID 9822598. 
  7. ^ Vadlamudi RK, Kumar R (December 2003). "P21-activated kinases in human cancer". Cancer Metastasis Reviews. 22 (4): 385–93. PMID 12884913. 
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  38. ^ 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. PMID 26554417. 
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External links[edit]