Serine/threonine-protein kinase PAK 4
Also known as: KIAA1142, PAK4
Function
Serine/threonine-protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell adhesion turnover, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN. Promotes kinase-independent stabilization of RHOU, thereby contributing to focal adhesion disassembly during cell migration.
Classification
- Family (Pfam)
- PF00786 PBD, PF00069 Pkinase
- InterPro
- CRIB_dom, CRIB_dom_sf, Kinase-like_dom_sf, PAK3-like, PAK_BD, Prot_kinase_dom, Protein_kinase_ATP_BS
- Functional cluster
- Serine/Threonine Protein Kinases
Experimental structures · PDB · 49
- 2BVA X-ray 2.30A
- 2CDZ X-ray 2.30A
- 2J0I X-ray 1.60A
- 2OV2 X-ray 2.10A
- 2Q0N X-ray 1.75A
- 2X4Z X-ray 2.10A
- 4APP X-ray 2.20A
- 4FIE X-ray 3.11A
- 4FIF X-ray 2.60A
- 4FIG X-ray 3.01A
- 4FIH X-ray 1.97A
- 4FII X-ray 2.00A
- … and 37 more
A predicted model is available from AlphaFold.
Gene Ontology · 26
- GO:0005912 adherens junction
- GO:0030054 cell junction
- GO:0005737 cytoplasm
- GO:0005829 cytosol
- GO:0005925 focal adhesion
- GO:0005794 Golgi apparatus
- GO:0005886 plasma membrane
- GO:0005524 ATP binding
- GO:0098641 cadherin binding involved in cell-cell adhesion
- GO:0004672 protein kinase activity
- GO:0106310 protein serine kinase activity
- GO:0004674 protein serine/threonine kinase activity
- GO:0030674 protein-macromolecule adaptor activity
- GO:0006915 apoptotic process
- GO:0016477 cell migration
- GO:0009267 cellular response to starvation
- GO:0007010 cytoskeleton organization
- GO:0035556 intracellular signal transduction
- GO:2000352 negative regulation of endothelial cell apoptotic process
- GO:0010897 negative regulation of triglyceride catabolic process
- GO:0045766 positive regulation of angiogenesis
- GO:0120183 positive regulation of focal adhesion disassembly
- GO:0050821 protein stabilization
- GO:0001558 regulation of cell growth
- GO:0043408 regulation of MAPK cascade
- GO:0007165 signal transduction
Drugs targeting this protein · 1
- PF-03758309 inhibitor
Related proteins · sequence + function similarity
- Serine/threonine-protein kinase PAK 4 0.98
- Serine/threonine-protein kinase PAK 6 0.84
- Serine/threonine-protein kinase PAK 6 0.83
- Serine/threonine-protein kinase PAK 6 0.77
- Serine/threonine-protein kinase H2 0.72
- Serine/threonine-protein kinase LATS2 0.71
- Serine/threonine-protein kinase LATS2 0.71
- Phototropin 0.70
- Serine/threonine-protein kinase H1 0.69
- Serine/threonine-protein kinase 25 0.69
- Serine/threonine-protein kinase H1 0.69
- Probable serine/threonine-protein kinase At1g54610 0.69
Co-cited proteins · studied together in the literature
- N-lysine methyltransferase SETD6 1 shared papers
- Bcl2-associated agonist of cell death 1 shared papers
- PAK4-inhibitor INKA1 1 shared papers
- PAK4-inhibitor INKA2 1 shared papers
- Rho guanine nucleotide exchange factor 2 1 shared papers
- Ras-related protein Rab-40A 1 shared papers
- Protein phosphatase Slingshot homolog 1 1 shared papers
- E3 ubiquitin-protein ligase SH3RF2 1 shared papers
- LIM domain kinase 1 1 shared papers
- Rho-related GTP-binding protein RhoU 1 shared papers
- LIM domain kinase 1 1 shared papers
- Tumor necrosis factor receptor type 1-associated DEATH domain protein 1 shared papers
Literature · 32 cited papers
- Oligomerization and Auto-methylation of the Human Lysine Methyltransferase SETD6. J. Mol. Biol. · 2018
- An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. Nat. Commun. · 2015
- PAK4 promotes kinase-independent stabilization of RhoU to modulate cell adhesion. J. Cell Biol. · 2015
- An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
- SH3RF2 functions as an oncogene by mediating PAK4 protein stability. Carcinogenesis · 2014
- Immunoaffinity enrichment and mass spectrometry analysis of protein methylation. Mol. Cell. Proteomics · 2014
- Toward a comprehensive characterization of a human cancer cell phosphoproteome. J. Proteome Res. · 2013
- System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. Sci. Signal. · 2011
- Initial characterization of the human central proteome. BMC Syst. Biol. · 2011
- Subgroup II PAK-mediated phosphorylation regulates Ran activity during mitosis. J. Cell Biol. · 2010
- Cdc42 regulates apical junction formation in human bronchial epithelial cells through PAK4 and Par6B. Mol. Biol. Cell · 2010
- p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration. J. Biol. Chem. · 2010
- … and 20 more in the literature graph