Pak protein kinases and their role in cancer

Abstract

Some of the characteristics of cancer cells are high rates of cell proliferation, cell survival, and the ability to invade surrounding tissue. The cytoskeleton has an essential role in these processes. Dynamic changes in the cytoskeleton are necessary for cell motility and cancer cells are dependent on motility for invasion and metastasis. The signaling pathways behind the reshaping and migrating properties of the cytoskeleton in cancer cells involve a group of Ras-related small GTPases and their effectors, including the p21-activated kinases (Paks). Paks are a family of serine/threonine protein kinases comprised of six isoforms (Pak 1–6), all of which are direct targets of the small GTPases Rac and Cdc42. Besides their role in cytoskeletal dynamics, Paks have recently been shown to regulate various other cellular activities, including cell survival, mitosis, and transcription. Paks are overexpressed and/or hyperactivated in several human tumors and their role in cell transformation makes them attractive therapeutic targets. Pak-targeted therapeutics may efficiently inhibit certain types of tumors and efforts to identify selective Pak-inhibitors are underway.

A Rac1/PAK1 cascade controls β-catenin activation in colon cancer cells

“…We thought to investigate whether another downstream effector of Rac1, P21-activated kinase (PAK), was involved. In supporting this hypothesis, both Rac1 and PAK1 were found overactivated in colon cancer samples (Esufali and Bapat, 2004;Kumar et al, 2006;Dummler et al, 2009).…”

“…Group I PAKs (PAK1, PAK2 and PAK3) were initially identified as effectors of the small GTPases Cdc42 and Rac1 (Manser et al, 1994), but could also be activated by diverse pathways (Bokoch, 2003;Kumar et al, 2006), whereas Group II PAKs (PAK4,PAK5 and PAK6) were identified more recently with their regulation less understood (Wells and Jones, 2010). PAKs have oncogenic functions in a broad range of cancers and their over-activation have been well documented (Kumar et al, 2006;Dummler et al, 2009;Molli et al, 2009). For example, PAK1 phosphorylates Merlin at Ser518 and inhibits its activity in neurofibromatosis (Xiao et al, 2002;Rong et al, 2004).…”

Rac1-dependent recruitment of PAK2 to G2phase centrosomes and their roles in the regulation of mitotic entry

“…PAK1-3 are downstream effector proteins of the small GTPases Rac1/Cdc42. 9,10 Binding of Rac1/ Cdc42 in their active GTP-bound state to the RBD abrogates the interaction of the kinase inhibitory domain (KID) with the kinase domain leading to kinase activation. Kinase activity is induced by either autophosphorylation in trans at pT423/402-PAK1/2 within the activation loop of the kinase domain or may involve a third-party kinase such as phosphoinositide-dependent protein kinase-1 (PDK1).…”

FRAX597, a Small Molecule Inhibitor of the p21-activated Kinases, Inhibits Tumorigenesis of Neurofibromatosis Type 2 (NF2)-associated Schwannomas

“…PAK1 has been reported to be widely overexpressed and/or hyperactivated in various types of benign and malignant cancers (6). PAK1 expression is up-regulated in 40 -50% of primary breast cancers (7,8).…”