PAK signalling during the development and progression of cancer

Abstract

p21-Activated kinases (PAKs) are positioned at the nexus of several oncogenic signalling pathways. Overexpression or mutational activation of PAK isoforms frequently occurs in various human tumours, and recent data suggest that excessive PAK activity drives many of the cellular processes that are the hallmarks of cancer. In this Review, we discuss the mechanisms of PAK activation in cancer, the key substrates that mediate the developmental and oncogenic effects of this family of kinases, and how small-molecule inhibitors of these enzymes might be best developed and deployed for the treatment of cancer.

Figure 1. Validated Pak substrates and their roles in the hallmarks of cancer

Substrates of group I and II Paks are listed according to their putative role in oncogenic signaling. In some cases (e.g., c-Raf), given substrates play roles in multiple cellular functions, but may be listed only once to avoid visual clutter. Pak substrates are included only if reported by more than one group or if the reported site of phosphorylation is represented in the PhosphoSitePlus database (http://www.phosphosite.org/homeAction.do). Abbreviations: CALD1, caldesmin 1; ER, estrogen receptor; FlnA, Filamin A; H3, histone 3; LIMK, LIM kinase; MLC, myosin light chain; MLCK, myosin light chain kinase; Plk1, polo-kinase-1; SSH, Slingshot; Stmn1, stathmin-1; Vim, Vimentin.

Figure 2. Role of Pak in growth signal autonomy and cell survival

Group I Paks are activated by both Cdc42 and Rac, whereas Group II Paks are activated only by Cdc42. Selected Pak substrates are depicted according to their role in oncogenic signaling. Phosphorylation sites, where known, are listed for each substrate. Dashed lines indicate that Pak has been implicated in activation of the substrate, but that the mechanism is uncertain.

Figure 3. Pak signaling in angiogenesis and modulation of vascular permeability

Paks control critical cellular events required for angiogenesis, including endothelial cell proliferation, survival, attachment and migration. In endothelial cells, the phosphorylation of BAD and RAF1 by Pak protects against apoptotic stimuli by promoting RAF1 translocation to mitochondria and the displacement of BAD/BCL2 complexes. As seen in other cellular contexts, in endothelial cells, the Erk pathway regulates cellular proliferation and migration when initiated by activation of Rac/Pak pathway. The control of vascular permeability by Pak is mediated by modulation of cellular contractility and cell:cell adhesion molecules. In one model, direct phosphorylation of myosin light chain (MLC) by Pak leads to increased contractility and increased endothelial permeability, as has been seen in certain experimental settings. Pak has also been proposed to disrupt endothelial cell:cell junctions by direct phosphorylation and subsequent internalization and degradation of VE cadherin. In another model, activated Pak phosphorylates and inhibits GEF-H1 (also known as ARHGEF2), leading to diminished RHOA/RHO-associated coiled-coil containing protein kinase (ROCK)/MLC activity, decreased contractility and decreased endothelial permeability, This model is consistent with data showing that Pak protects against an increase in permeability in a hypoxia induced pulmonary hypertension model and in a Pak2a knockout zebrafish model (dotted lines).

Figure 4. Specificity of Pak inhibitors

The human kinome is represented on a radar plot. The Pak family is oriented to 12 o’clock, emphasized by a red marking. The length of gray areas emanating from the bulls-eye represents the degree of kinase inhibition by each inhibitor shown below. Kinase families are indicated by different colors, as shown in the key to the right of the diagram: TK – Tyrosine kinase; TKL – Tyrosine kinase-like; STE – Homologs of yeast Sterile 20 kinases; CK1 – Casein kinase 1; AGC –Containing PKA, PKG, PKC families; CAMK – Calcium/calmodulin-dependent protein kinase; CMGC –Containing CDK, MAPK, GSK3, CLK families; ATYPICAL – Atypical protein kinase. Primary specificity data are derived from References , , , and .