Regulation of Cancer Metastasis by PAK2

Abstract

PAK2 is a serine-threonine kinase and a member of the p21-activated kinase (PAK) family. PAK2 is activated by GTP-bound rho family GTPases, Rac, and Cdc42, and it regulates actin dynamics, cell adhesion to the extracellular matrix, and cell motility. In various types of cancers, PAK2 has been implicated in the regulation of cancer cell proliferation, cell cycle, and apoptosis. In addition, recent studies have shown that PAK2 plays an important role in cancer cell metastasis, indicating PAK2 as a potential therapeutic target. This review discusses recent discoveries on the functions of PAK2 in the regulation of various types of cancers. A better understanding of the mechanisms of function of PAK2 will facilitate future development of cancer therapies.

Keywords: PAK2; apoptosis; cancer metastasis; cell cycle; rho family GTPases.

Figure 1

Structure and activation of PAK2. (A). The domain structure of the PAK2 protein. (B). Two different mechanisms that activate PAK2. AID: auto-inhibitory domain; Cdc42: cell division cycle 42, PBD: p21 binding domain; PAK2: p21-activated kinase 2; Rac1: Ras-related C3 botulinum toxin substrate 1.

Figure 2

Phosphorylation of the substrate proteins by PAK2 regulates various cellular functions. PAK2 phosphorylates key proteins that are involved in cell cycle, apoptosis, and motility. Akt: Ak strain transforming; Bcl-2: B-cell lymphoma 2; Bad: Bcl-2 associated agonist of cell death; c-Abl: Abelson murine leukemia viral homolog 1; Cdc42: Cell division cycle 42, CDK2: cyclin-dependent kinase 2; LIMK: LIM kinase; MLCK: myosin light-chain kinase; MAPK: mitogen-activated protein kinase; miR: microRNA; Myc: myelocytomatosis oncogene; PI3K: phosphoinositide 3-kinases; Rac1: Ras-related C3 botulinum toxin substrate 1; RLC: regulatory light chains; STAT5: signal transducer and activator of transcription 5.

Figure 3

Mechanisms of action of PAK2 in the regulation of different signaling pathways in different cancers. The red arrow indicates that CDK12 activates the MAPK signaling pathway by directly binding to and phosphorylating PAK2 at T134/T169, thereby promoting gastric cancer progression. Upward arrows indicate the activation of PAK2. Akt: Ak strain transforming; ACSL4: Acyl-CoA synthetase long-chain family member 4; CDK2: cyclin-dependent kinase 12; CASP: caspase; FAK: focal adhesion kinase; PYK2: FAK-related proline-rich tyrosine kinase 2; HSP90: heat-shock protein 90; LIMK: LIM domain kinase; mTOR: mechanistic target of rapamycin; MAPK: mitogen-activated protein kinase; MCM7: minichromosome maintenance complex component 7; Mlck: myosin light-chain kinases; PI3K: phosphoinositide 3-kinases; PKM2: pyruvate kinase M2; Raf: rapidly accelerated fibrosarcoma; SOX2: SRY (sex-determining region Y)-box 2; STX17: Syntaxin 17.