The role of PAK6 in HGF-induced prostate cancer cell migration

Abstract

Cell migration plays a significant role in carcinoma metastasis in which cancer cells move from the primary site and establish tumours at a secondary location. During tumour progression cancer cells can assume a migratory phenotype which is characterised by cell-cell dissociation and single cells adopting a migratory morphology. Hepatocyte growth factor (HGF) signalling is known to induce cell-cell dissociation and is associated with prostate carcinoma progression. HGF-induced cell-cell dissociation and migration require the activity of the Rho family GTPases Rho A, Racl and Cdc42 and their effector proteins, p21-activated kinases (PAKs), which are a family of mammalian serine/threonine protein kinases. PAK6, a PAK family member, is over-expressed in prostate cancer but little is known about its function in cells. This project investigated the potential role of PAK6 downstream of HGF in DU145 colony-forming prostate cancer cells. These cells exhibit prominent epithelial-cadherin (E-cadherin)-associated cell-cell junctions and ’scatter’ upon HGF stimulation. Studies described here show that HGF addition increases PAK6 autophosphorylation and that PAK6 depletion inhibits HGF-induced DU145 cell scattering where these cells retain junctional E-cadherin. Moreover, PAK6 over-expression induces cell elongation and colony escape in unstimulated DU145 cells and PAK6 localises to E-cadherin positive cell junctions. Functional studies identified IQ motif containing GTPase activating protein 1 (IQGAP1) as a PAK6 binding partner in DU145 cells. Furthermore, PAK6 interacts with IQGAP1 in an HGF-dependent manner and both proteins act synergistically to induce cell colony escape. Additional studies suggest a complex relationship between IQGAP1, PAK6 and E-cadherin during HGF-induced junctional disassembly where IQGAP1 mediates PAK6 activity.

Date of Award	1 Oct 2012
Original language	English
Awarding Institution	King's College London
Supervisor	Claire Wells (Supervisor) & Anne Ridley (Supervisor)