p21-Activated Kinase 3 (PAK3) Is an AP-1 Regulated Gene Contributing to Actin Organisation and Migration of Transformed Fibroblasts

Abstract

Activating Protein 1 (AP-1) plays a vital role in cell proliferation, differentiation and apoptosis. While de-regulation of AP-1 has been linked to many cancers, little is known regarding its downstream transcriptional targets that associate with cellular transformation. Previous studies identified PAK3, a serine/threonine kinase, as a potential AP-1 target gene. PAK3 has been implicated in a variety of pathological disorders and over-expression of other PAK-family members has been linked to cancer. In this study, we investigate AP-1 regulation of PAK3 expression and the role of PAK3 in cJun/AP-1-associated cellular transformation. Our results showed elevated PAK3 expression at both the mRNA and protein level in cJun-over-expressing Rat1a fibroblasts, as well as in transformed human fibroblasts. Elevated PAK3 expression in cJun/AP-1 over-expressing cells associated with a significant increase in PAK3 promoter activation. This increased promoter activity was lost when a single putative Jun binding site, which can bind AP-1 directly both in vitro and in vivo, was mutated. Further, inhibition of PAK3 using siRNA showed a regression in the cell morphology, migratory potential and actin organisation associated with AP-1 transformed cells. Our study is a first to describe a role for AP-1 in regulating PAK3 expression and suggest that PAK3 is an AP-1 target required for actin organization and migration observed in transformed cells.

Inhibitory effect of SLIT2 on granulosa cell proliferation mediated by the CDC42-PAKs-ERK1/2 MAPK pathway in the prehierarchical follicles of the chicken ovary

“…Although direct evidence proving that PAK2 and PAK3 are implicated in the regulation of the ovarian GC proliferation is lacking, PAK2 has been shown to bind and phosphorylate caspase-7, which fractionally decreases its activity and thereby inhibits cellular apoptosis in human breast carcinoma tissue 41 . Furthermore, PAK3 expression is required for cell migration and actin organization in transformed fibroblasts 42 . The over-expression of the PAK3 protein has been associated with the proliferation of mouse corticotrophs 43 .…”

PAK signalling during the development and progression of cancer

“…The expression of PAK2 and PAK4 has also been shown to be regulated by miRNAs 11–13 . Finally, PAK3 transcription was recently reported to be regulated by AP-1 14 . Given reports that expression of certain PAK genes is increased by oncogenic signals 15 , we can expect that future work will uncover additional regulators of PAK transcription or translation that are relevant to cancer.…”

Deciphering the link between PI3K and PAK: An opportunity to target key pathways in pancreatic cancer?

“…Conversely, PAK inhibition leads to reduced migratory and less invasive potential of cancer cells [93–99]. …”

“…It has also been reported that the promotion of invasion through extracellular matrix degradation can be mediated by PAK-induced secretion of matrix metalloproteinases MMP-1, MMP-2, MMP-3 and MMP-9 [ 77 , 92 , 93 ]. Conversely, PAK inhibition leads to reduced migratory and less invasive potential of cancer cells [ 93 – 99 ].…”