PAK4 interacts with p85 alpha: implications for pancreatic cancer cell migration

Abstract

It has been reported that p21-activated kinase 4 (PAK4) is amplified in pancreatic cancer tissue. PAK4 is a member of the PAK family of serine/threonine kinases, which act as effectors for several small GTPases, and has been specifically identified to function downstream of HGF-mediated c-Met activation in a PI3K dependent manner. However, the functionality of PAK4 in pancreatic cancer and the contribution made by HGF signalling to pancreatic cancer cell motility remain to be elucidated. We now find that elevated PAK4 expression is coincident with increased expression levels of c-Met and the p85α subunit of PI3K. Furthermore, we demonstrate that pancreatic cancer cells have a specific motility response to HGF both in 2D and 3D physiomimetic organotypic assays; which can be suppressed by inhibition of PI3K. Significantly, we report a specific interaction between PAK4 and p85α and find that PAK4 deficient cells exhibit a reduction in Akt phosphorylation downstream of HGF signalling. These results implicate a novel role for PAK4 within the PI3K pathway via interaction with p85α. Thus, PAK4 could be an essential player in PDAC progression representing an interesting therapeutic opportunity.

PAK4 inhibition improves PD-1 blockade immunotherapy

“…In addition to regulating WNT/β-catenin signaling 15,18 , PAK4 can promote tumorigenesis by altering different oncogenic pathways, including those that have been previously involved in immune cell exclusion 16 . For instance, PAK4 can increase PI3K/AKT signaling in different cancer malignancies by directly binding to PI3K ) WT anti-PD-1 a b c and increasing AKT phosphorylation [42][43][44][45] . Interestingly, PAK4 also presents kinase-independent functions.…”

Role of PI3K/AKT pathway in cancer: the framework of malignant behavior

“…In contrast to the well-known genetically inactivated of P16 (90%), TP53 (75%), DPC4 (55%), as well as activated oncogene KRAS (90%) and Her2 (4-50%) in PDAC [155][156][157][158][159], the overall genetic aberrations of PI3K/AKT members (PIK3CA, 2.3% and PTEN 1.9%, Table 1) are less frequently. Interestingly, pancreatic cell plasticity and cancer initiation induced by Kras is completely dependent on wild-type p110α [160], and PAK4 interacts with p85α can affect the migration of PDAC cells [161]. Significantly, the mutations of PIK3CG in PDAC are also revealed [156].…”

PAK4 Pathway as a Potential Therapeutic Target in Pancreatic Cancer

“…In PDAC cells, depletion of PAK4 leads to a reduction in anchorage-independent growth and furthermore activated PAK4 leads to increased migration [9]. Furthermore, PAK4 depletion results change in cell morphology suggesting actin cytoskeletal reorganization and both reduced 2D migration and 3D invasion.…”

“…PAK4 has been shown to bind to the p85 component of PI3K and PAK4 depletion leads to reduced phosphorylation of AKT, an important serine-threonine kinase in the PI3K signaling pathway [9]. In addition PAK4 can also lead to reduced ERK activation, part of the MAPK pathway.…”

“…Following its discovery, several research efforts have sought to interrogate its role in carcinogenesis where it is often overexpressed. PAK4 can mediate cell migration and cell proliferation [9]. There is also evidence that PAK4 regulates the cell cycle and interact with several pertinent oncogenic pathways including the MAPK pathway and the PI3K pathway [10].…”