title: 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.
authors.affiliation: Division of Cancer Studies, King's College London, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: King
authors.affiliation: Division of Cancer Studies, King's College London, UK.
authors.forename: Kiruthikah
authors.initials: K
authors.lastname: Thillai
authors.affiliation: Division of Cancer Studies, King's College London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Whale
authors.affiliation: Barts Cancer Institute, a CRUK centre of Excellance, Queen Mary University of London, UK.
authors.forename: Prabhu
authors.initials: P
authors.lastname: Arumugam
authors.affiliation: Dept of Haematopathology Oncology Diagnostic Service, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Hesham
authors.initials: H
authors.lastname: Eldaly
authors.affiliation: Barts Cancer Institute, a CRUK centre of Excellance, Queen Mary University of London, UK.
authors.forename: Hemant M
authors.initials: HM
authors.lastname: Kocher
authors.affiliation: Division of Cancer Studies, King's College London, UK.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Wells
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D005810:Multigene Family; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; C116367:PAK4 protein, human; D058543:Class Ia Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D054462:p21-Activated Kinases; D018631:ras Proteins