PAK4
Description
The PAK4 (p21 (RAC1) activated kinase 4) is a protein-coding gene located on chromosome 19.
PAK4, a member of the Group II PAK family of serine/threonine kinases, is encoded by the PAK4 gene in humans. It is localized in the cytoplasm and nucleus, regulating cytoskeletal remodeling, signaling, and gene expression. PAK4's functions affect cell motility, invasion, metastasis, and growth, impacting both physiological and pathological processes, including cancer, where it is often overexpressed or hyperstimulated. PAK4 was discovered in 1998 by Minden A. and colleagues using a PCR-based strategy from a cDNA library prepared from Jurkett cells. The human PAK4 gene is approximately 57-kb long with 13 exons, generating 12 transcripts, including 10 coding transcripts predicting proteins ranging from 438 to 591 amino acids in length. The remaining two transcripts are non-coding. In contrast to human PAK4, murine PAK4 has four transcripts – two coding for 593 amino acid long polypeptides and two non-coding RNA transcripts.
PAK4 is a serine/threonine protein kinase involved in diverse signaling pathways, including cytoskeleton regulation, cell migration, growth, proliferation, and survival. Its activation by factors like growth factor receptors or active CDC42 and RAC1 triggers a conformational change followed by autophosphorylation at multiple serine/threonine residues. PAK4 inactivates protein phosphatase SSH1 through phosphorylation, leading to increased inhibitory phosphorylation of cofilin, an actin binding/depolymerizing factor. Reduced cofilin activity stabilizes actin filaments. PAK4 also phosphorylates LIMK1, another kinase that inhibits cofilin activity. By phosphorylating integrin beta5/ITGB5, PAK4 regulates cell motility. Additionally, PAK4 phosphorylates ARHGEF2, activating the downstream target RHOA, which plays a role in focal adhesion assembly and actin stress fiber regulation. PAK4 promotes cell survival by phosphorylating BAD, a BCL2 antagonist of cell death. Moreover, it inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase-independent manner. PAK4 contributes to cell-cycle progression by controlling CDKN1A levels and phosphorylating RAN.
PAK4 is also known as -.
Associated Diseases
- hereditary breast ovarian cancer syndrome
- prostate cancer
- breast cancer
- pachyonychia congenita
- glioblastoma
- cancer
