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XB-ART-47132
PLoS One January 1, 2013; 8 (5): e65294.
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Potassium-chloride cotransporter 3 interacts with Vav2 to synchronize the cell volume decrease response with cell protrusion dynamics.

Salin-Cantegrel A , Shekarabi M , Rasheed S , Charron FM , Laganière J , Gaudet R , Dion PA , Lapointe JY , Rouleau GA .


Abstract
Loss-of-function of the potassium-chloride cotransporter 3 (KCC3) causes hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a severe neurodegenerative disease associated with defective midline crossing of commissural axons in the brain. Conversely, KCC3 over-expression in breast, ovarian and cervical cancer is associated with enhanced tumor cell malignancy and invasiveness. We identified a highly conserved proline-rich sequence within the C-terminus of the cotransporter which when mutated leads to loss of the KCC3-dependent regulatory volume decrease (RVD) response in Xenopus Laevis oocytes. Using SH3 domain arrays, we found that this poly-proline motif is a binding site for SH3-domain containing proteins in vitro. This approach identified the guanine nucleotide exchange factor (GEF) Vav2 as a candidate partner for KCC3. KCC3/Vav2 physical interaction was confirmed using GST-pull down assays and immuno-based experiments. In cultured cervical cancer cells, KCC3 co-localized with the active form of Vav2 in swelling-induced actin-rich protruding sites and within lamellipodia of spreading and migrating cells. These data provide evidence of a molecular and functional link between the potassium-chloride co-transporters and the Rho GTPase-dependent actin remodeling machinery in RVD, cell spreading and cell protrusion dynamics, thus providing new insights into KCC3''s involvement in cancer cell malignancy and in corpus callosum agenesis in HMSN/ACC.

PubMed ID: 23724134
PMC ID: PMC3665532
Article link: PLoS One
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: actl6a cttn rho slc12a4 slc12a5 slc12a6 vav1 vav2 vav3


Article Images: [+] show captions
References [+] :
Adragna, Regulation of K-Cl cotransport: from function to genes. 2005, Pubmed