Abstract |
Hepatocyte growth factor (HGF) is associated with tumour progression and increases the invasiveness of prostate carcinoma cells. Cell migration and invasion requires reorganisation of the actin cytoskeleton; processes mediated by the Rho family GTPases. p21 activated kinase 4 (PAK4), an effector of the Rho family protein Cdc42, is activated downstream of HGF. We report here the novel finding that in prostate cancer cells PAK4 binds to and phosphorylates LIM kinase 1 (LIMK1) in an HGF-dependent manner. We show for the first time that variations in the level of PAK4 expression change the level of cofilin phosphorylation in cells, a change we correlate with LIMK1 activity, cell morphology and migratory behaviour. We identify for the first time a direct and localised interaction between PAK4 and LIMK1 within cells using FRET: FLIM. Moreover we show here that HGF mediates this interaction which is concentrated in small foci at the cell periphery. PAK4 and LIMK1 act synergistically to increase cell migration speed, whilst a reduction in PAK4 expression decreases cell speed. It is well established that unphosphorylated (active) cofilin is a required to drive cell migration. Our results support a model whereby HGF-stimulated cell migration also requires a cofilin phosphorylation step that is mediated by PAK4.
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Authors | Tasneem Ahmed, Kerry Shea, John R W Masters, Gareth E Jones, Claire M Wells |
Journal | Cellular signalling
(Cell Signal)
Vol. 20
Issue 7
Pg. 1320-8
(Jul 2008)
ISSN: 0898-6568 [Print] England |
PMID | 18424072
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Actin Depolymerizing Factors
- Hepatocyte Growth Factor
- PAK4 protein, human
- LIMK1 protein, human
- Lim Kinases
- p21-Activated Kinases
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Topics |
- Actin Depolymerizing Factors
(metabolism)
- Cell Line, Tumor
- Cell Movement
(drug effects)
- Cell Polarity
(drug effects)
- Hepatocyte Growth Factor
(pharmacology)
- Humans
- Lim Kinases
(metabolism)
- Male
- Models, Biological
- Phosphorylation
(drug effects)
- Prostatic Neoplasms
(enzymology, pathology)
- Protein Binding
(drug effects)
- p21-Activated Kinases
(metabolism)
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