PAK signaling in cancer

Abstract

Transformation of a normal cell to a cancer cell is caused by mutations in genes that regulate proliferation, apoptosis, and invasion. Small GTPases such as Ras, Rho, Rac and Cdc42 orchestrate many of the signals that are required for malignant transformation. The p21-activated kinases (PAKs) are effectors of Rac and Cdc42. PAKs are a family of serine/threonine protein kinases comprised of six isoforms (PAK1-6), and they play important roles in cytoskeletal dynamics, cell survival and proliferation. They act as key signal transducers in several cancer signaling pathways, including Ras, Raf, NFκB, Akt, Bad and p53. Although PAKs are not mutated in cancers, they are overexpressed, hyperactivated or amplified in several human tumors and their role in cell transformation make them attractive therapeutic targets. This review discusses the evidence that PAK is important for cell transformation and some key signaling pathways it regulates. This review primarily discusses Group I PAKs (PAK1, PAK2 and PAK3) as Group II PAKs (PAK4, PAK5 and PAK6) are discussed elsewhere in this issue (by Minden).

Figure 1. PAKs and cancer hallmarks. PAKs are effectors of Rac/Cdc42 and play a key role in some of cancer hallmarks, including proliferative signaling, resisting cell death, activating invasion and metastasis and inducing angiogenesis. PAKs can regulate cell proliferation through the Raf/Mek pathway. Cell motility can be affected by PAKs phosphorylation of cytoskeletal targets, such as LIMK, which phosphorylates cofilin. PAK1 also phosphorylates Bad directly and indirectly via Raf-1, thus promoting cell survival by anti-apoptosis. NFκB is regulated by PAK indirectly to promote cell survival. Other cancer hallmarks are also affected indirectly by PAKs.

Figure 2. PAK phosphorylation sites. Activated PAK proteins phosphorylate a variety of substrates on serine/threonine residues, preferably in the context of basic residues such as K/R, R/X, X and S/T, to bring about cell survival and migration, cytoskeleton remodeling and gene regulation. Shown here are the sequences of phosphorylation sites of several PAK substrates. Consensus sequence is also shown. X can be acidic, basic or neutral amino acid.