Targeting PAK etk…

Abstract

B i o s c i e n c e . N o t f o r d i s t r i b u t i o n .[Cancer Biology & Targeting PAK etk… PAK kinases are versatile proteins that have been shown to be involved in many cellular signaling pathways including regulation of cytoskeletal reorganization, cell transformation, and survival. Though the first p21-activated kinase member (PAK1) was identified less than 10 years ago, 1 our understanding of these kinases has increased tremendously since then. The PAKs are a family of serine-threonine kinases with six known isoforms. They can be divided into two groups based on structural similarities. Group A includes PAK1 (αPAK), PAK2(γPAK) and PAK3(βPAK), and group B consists of PAK4, PAK5 and PAK6. Group A PAKs contain an N-terminal regulatory domain and a C-terminal kinase domain. Within the N-terminal domain is the p21-binding domain (PBD), which binds the small GTPases Rac and Cdc42 to activate the kinase domain by releasing it from autoinhibition. Flanking the PBD domain are two SH3-binding regions which bind the adaptor protein Nck 2 and a Rac GEF Pix, 3 respectively. Like group A PAKs, group B PAKs also contain the PBD domain and C-terminal kinase domain, but they do not have SH3-binding regions for Nck and Pix. 4 Furthermore, the PBD and kinase domains of group B PAKs only have relatively low (about 50%) sequence identity with group A PAKs. In addition to activation by small GTPases, PAKs are activated by p21-independent mechanisms. The p21-dependent mechanism, as suggested by the naming of PAK, is the one by which PAK was first identified 1 and probably represents the main mechanism for PAK activation.Because Rac and Cdc42 are two Rho family members downstream of the Ras oncogene, there has been a keen interest in determining if PAK is involved in oncogenic transformation especially since Ras is one of the most frequently mutated oncogenes. To date, evidence has accumulated from many labs suggesting that PAK isoforms from both group A and B promote cell transformation. Tang et al. first showed that expression of dominant negative PAK1 blocked Ras transformation of Rat-1 fibroblasts 5 and Schwann cells. 6 Expression of dominant negative PAK1 in a highly invasive breast cancer cell line also suppressed its invasiveness and motility, 7 although PAK2 may be more relevant in breast cancer. 8 PAK4 is overexpressed in about 75% of tumor cell lines and dominant negative mutants of PAK4 also inhibit cell transformation. 9,10 Both group A and B family members also protect cells by inhibiting apoptosis. The mechanism of protection involves crosstalk to the Akt pathway. [11][12][13][14] Together, these studies suggest PAK is important for oncogenic cell transformation and has the potential to be a molecular target for suppressing cell transformation caused by Ras and related genes.Ras itself and intermediates in two major Ras effector pathways (PI 3K cascade and Raf/MEK/MAPK cascade) have been considered as potential pharmacologic targets of Ras-induced cell transformation. Another category of drugs are farnesyl transf...

Increased p21-activated kinase-1 expression is associated with invasive potential in uveal melanoma

“…PAK is important for oncogenic cell transformation and has the potential to be a molecular target for suppressing cell transformation caused by Ras and related genes [66]. PAK1 has been shown to play a central role in regulating cell motility and invasiveness in a number of cancers, with increased levels reported in breast [20,21] and colorectal [22] carcinomas, with in-vitro expression of dominant-negative PAK1 in a highly invasive breast cancer cell line shown to suppress its invasiveness and motility [67].…”

P-21-activated protein kinase-1 functions as a linker between insulin and Wnt signaling pathways in the intestine

“…PAK-1 was initially recognized as a downstream target of the Rho family GTPases, Rac1 and Cdc42, in regulating actin remodeling (Knaus and Bokoch, 1998;Zhou and Field, 2004;Arias-Romero and Chernoff, 2008). PAK-1 can also be activated by Akt (Zhou et al, 2003), or become directly phosphorylated/activated by PI3K (Tsakiridis et al, 1996) or phosphoinositide-dependent kinase isozyme-1 on Thr 423 (King et al, 2000), without requiring Akt.…”