The scaffolding protein GRASP-Tamalin directly binds to Dock180 as well as to cytohesins facilitating GTPase crosstalk in epithelial cell migrationReportar como inadecuado

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BMC Cell Biology

, 14:9

Cell signaling pathways and networks


BackgroundThe transition of epithelial cells from their normal non-motile state to a motile one requires the coordinated action of a number of small GTPases. We have previously shown that epithelial cell migration is stimulated by the coordinated activation of Arf and Rac GTPases. This crosstalk depends upon the assembly of a multi-protein complex that contains the Arf-activating protein cytohesin 2-ARNO and the Rac activating protein Dock180. Two scaffolding proteins that bind directly to cytohesin 2 organize this complex.

ResultsWe now have found that Rac activation in response to hepatocyte growth factor HGF requires cytohesin 2 and Dock180. GRASP-Tamalin is one of the scaffolds that builds the complex containing cytohesin 2 and Dock180. We determine here that the Ala-Pro rich region of GRASP directly interacts with the SH3 domain of Dock180. By binding to both cytohesin 2-ARNO and Dock180, GRASP bridges the guanine nucleotide exchange factors GEFs that activate Arf and Rac, thereby promoting Arf-to-Rac signaling. Furthermore, we find that knockdown of GRASP impairs hepatocyte growth factor HGF-stimulated Rac activation and HGF-stimulated epithelial migration.

ConclusionsGRASP binds directly both cytohesin 2 and Dock180 to coordinate their activities, and by doing so promotes crosstalk between Arf and Rac.

KeywordsCytohesin GRASP Tamalin Dock180 Arf6 and Rac1 AbbreviationsARNOArf nucleotide binding site opener

CNK3Connector enhancer of KSR 3

CSF-1Colony stimulating factor 1

DH-PHDbl homology–pleckstrin homology

EGFEpithelial growth factor

FGFFibroblast growth factor

GAPGTPase activating protein

GAPDHGlyceraldehyde 3-phosphate dehydrogenase

GEFGuanine nucleotide exchange factor

GRASPGrp1 associated scaffold protein

Grp1General receptor for phosphoinositides-1

HGFHepatocyte growth factor

IPCEFInteracting protein for cytohesin exchange factor

MDCKMadin-Darby canine kidney

NEDD9Neural precursor cell expressed developmentally down-regulated protein 9

PBSPhosphate buffered saline

PDGFPlatelet derived growth factor

SFScatter factor

SH3Src homology 3

TGF-βTransforming growth factor beta

VEGFVascular endothelial growth factor.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2121-14-9 contains supplementary material, which is available to authorized users.

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Autor: Myriam A Attar - Lorraine C Santy


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