Serine/threonine-protein kinase PAK 4

Definition:

Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, 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.

References:

[1]. J Qu, et al. Activated PAK4 regulates cell adhesion and anchorage-independent growth. Mol Cell Biol. 2001 May;21(10):3523-33. [Content Brief]

[2]. Yohendran Baskaran, et al. An in cellulo-derived structure of PAK4 in complex with its inhibitor Inka1. Nat Commun. 2015 Nov 26;6:8681. [Content Brief]

[3]. Guillaume Bompard, et al. Subgroup II PAK-mediated phosphorylation regulates Ran activity during mitosis. J Cell Biol. 2010 Sep 6;190(5):807-22. [Content Brief]

[4]. N Gnesutta, et al. The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis. J Biol Chem. 2001 Apr 27;276(17):14414-9. [Content Brief]

[5]. Juliana Soosairajah, et al. Interplay between components of a novel LIM kinase-slingshot phosphatase complex regulates cofilin. EMBO J. 2005 Feb 9;24(3):473-86. [Content Brief]

[6]. Zhilun Li, et al. p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration. J Biol Chem. 2010 Jul 30;285(31):23699-710. [Content Brief]

[7]. Nerina Gnesutta, et al. Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4. Mol Cell Biol. 2003 Nov;23(21):7838-48. [Content Brief]

[8]. Sean W Wallace, et al. Cdc42 regulates apical junction formation in human bronchial epithelial cells through PAK4 and Par6B. Mol Biol Cell. 2010 Sep 1;21(17):2996-3006. [Content Brief]

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