Dataset Information

The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration.

ABSTRACT: Asef2 is a recently identified Rho-family guanine nucleotide exchange factor (GEF) that has been implicated in the modulation of actin, but its function in cell migration and adhesion dynamics is not well understood. In this study, we show that Asef2 is an important regulator of cell migration and adhesion assembly and disassembly (turnover). Asef2 localizes with actin at the leading edge of cells. Knockdown of endogenous Asef2 impairs migration and significantly slows the turnover of adhesions. Asef2 enhances both Rac1 and Cdc42 activity in HT1080 cells, but only Rac1 is crucial for the Asef2-promoted increase in migration and adhesion turnover. Phosphoinositide 3-kinase (PI3K) and the serine/threonine kinase Akt are also essential for the Asef2-mediated effects on migration and adhesion turnover. Consistent with this, Asef2 increases the amount of active Akt at the leading edge of cells. Asef2 signaling leads to an overall decrease in Rho activity, which is crucial for stimulating migration and adhesion dynamics. Thus, our results reveal an important new role for Asef2 in promoting cell migration and rapid adhesion turnover by coordinately regulating the activities of Rho-family GTPases.

SUBMITTER: Bristow JM

PROVIDER: S-EPMC2787464 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration.

Bristow Jeanne M JM Sellers Meredith H MH Majumdar Devi D Anderson Bridget B Hu Lan L Webb Donna J DJ

Journal of cell science 20091124 Pt 24

Asef2 is a recently identified Rho-family guanine nucleotide exchange factor (GEF) that has been implicated in the modulation of actin, but its function in cell migration and adhesion dynamics is not well understood. In this study, we show that Asef2 is an important regulator of cell migration and adhesion assembly and disassembly (turnover). Asef2 localizes with actin at the leading edge of cells. Knockdown of endogenous Asef2 impairs migration and significantly slows the turnover of adhesions. ...[more]

PMID: 19934221

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Project description:Focal adhesions are protein complexes that anchor cells to the extracellular matrix. During migration, the growth and disassembly of these structures are spatiotemporally regulated, with new adhesions forming at the leading edge of the cell and mature adhesions disassembling at the rear. Signalling proteins and structural cytoskeletal components tightly regulate adhesion dynamics. Paxillin, an adaptor protein within adhesions, is one of these proteins. Its phosphorylation at serine 273 (S273) is crucial for maintaining fast adhesion assembly and disassembly. Paxillin is known to bind to a GIT1-?PIX-PAK1 complex, which increases the local activation of the small GTPase Rac. To understand quantitatively the behaviour of this system and how it relates to adhesion assembly/disassembly, we developed a mathematical model describing the dynamics of the small GTPases Rac and Rho as determined by paxillin S273 phosphorylation. Our model revealed that the system possesses bistability, where switching between uninduced (active Rho) and induced (active Rac) states can occur through a change in rate of paxillin phosphorylation or PAK1 activation. The bistable switch is characterized by the presence of memory, minimal change in the levels of active Rac and Rho within the induced and uninduced states, respectively, and the limited regime of monostability associated with the uninduced state. These results were validated experimentally by showing the presence of bimodality in adhesion assembly and disassembly rates, and demonstrating that Rac activity increases after treating Chinese Hamster Ovary cells with okadaic acid (a paxillin phosphatase inhibitor), followed by a modest recovery after 20 min washout. Spatial gradients of phosphorylated paxillin in a reaction-diffusion model gave rise to distinct regions of Rac and Rho activities, resembling polarization of a cell into front and rear. Perturbing several parameters of the model also revealed important insights into how signalling components upstream and downstream of paxillin phosphorylation affect dynamics.

Dataset Information

The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration.

Publications

The Rho-family GEF Asef2 activates Rac to modulate adhesion and actin dynamics and thereby regulate cell migration.

Similar Datasets

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