Molecular Pathways: Targeting RAC–p21-Activated Serine–Threonine Kinase Signaling in RAS-Driven Cancers

Abstract

Cancers driven by oncogenic Ras proteins encompass some of the most deadly human cancer types, and there is a pressing need to develop therapies for these diseases. While recent studies suggest that mutant Ras proteins may yet be druggable, the most promising and advanced efforts involve inhibitors of Ras effector signaling. Most efforts to target Ras signaling have been aimed at the ERK mitogen-activated protein kinase and the phosphatidylinositol 3-kinase signaling networks. However, to date, no inhibitors of these Ras effector pathways have been effective against RAS mutant cancers. This ineffectiveness is due, in part, to the involvement of additional effectors in Ras-dependent cancer growth, such as the Rac small GTPase and the p21-activated serine-threonine kinases (PAK). PAK proteins are involved in many survival, cell motility, and proliferative pathways in the cell and may present a viable new target in Ras-driven cancers. In this review, we address the role and therapeutic potential of Rac and Group I PAK proteins in driving mutant Ras cancers.

PREX1 Protein Function Is Negatively Regulated Downstream of Receptor Tyrosine Kinase Activation by p21-activated Kinases (PAKs)

“…Our results further implicate PREX1 in these signaling pathways, demonstrating that it is targeted by downstream kinases, such as PAKs, to reduce its GEF activity. The importance of RTK signaling in cancer is well studied, and additionally, there is an emerging interest in targeting PAKs in cancer (37). We have now identified PAK-dependent negative feedback for both PREX1 and PREX2, and these signaling mechanisms may need to be considered when determining how to most effectively utilize PAK inhibitors in patients.…”

p21-activated Kinases (PAKs) Mediate the Phosphorylation of PREX2 Protein to Initiate Feedback Inhibition of Rac1 GTPase

“…Furthermore, similar to mTORC1-dependent negative feedback, PAK phosphorylation of PREX2 could have important therapeutic implications. PAK inhibitors are currently being evaluated as cancer therapeutics, and if PAK negative regulation of PREX2 is playing a significant role in insulin signaling, or more generally in Rac1 activation, then it may be important to consider in the context of certain cancers (75). For example, a tumor with PREX2 overexpression may not respond well to PAK inhibitors, which could increase PREX2 GEF activity toward Rac1.…”

PREX1 integrates G protein-coupled receptor and phosphoinositide 3-kinase signaling to promote glioblastoma invasion

“…GTP-Rac directly binds to and activates PAK1, PAK2 and PAK3 kinases, which control multiple aspects of cell behaviour including F-actin polymerization [35]. The activation of PAK1/2 by Rac can be monitored by the autophosphorylation of PAK1/2 on S144/S141 [36].…”