The Ras-related GTPase Rap1 stimulates integrin-mediated adhesion and spreading in various mammalian cell types. Here, we demonstrate that Rap1 regulates cell spreading by localizing guanine nucleotide exchange factors (GEFs) that act via the Rho family GTPase Rac1. Rap1a activates Rac1 and requires Rac1 to enhance spreading, whereas Rac1 induces spreading independently of Rap1. Active Rap1a binds to a subset of Rac GEFs, including VAV2 and Tiam1 but not others such as SWAP-70 or COOL-1. Overexpressed VAV2 and Tiam1 specifically require Rap1 to promote spreading, even though Rac1 is activated independently of Rap1. Rap1 is necessary for the accumulation of VAV2 in membrane protrusions at the cell periphery. In addition, if VAV2 is artificially localized to the cell edge with the subcellular targeting domain of Rap1a, it increases cell spreading independently of Rap1. These results lead us to propose that Rap1 promotes cell spreading by localizing a subset of Rac GEFs to sites of active lamellipodia extension.
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11 October 2004
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October 11 2004
Rap1 promotes cell spreading by localizing Rac guanine nucleotide exchange factors
William T. Arthur,
William T. Arthur
1Fred Hutchinson Cancer Research Center, Seattle, WA 98109
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Lawrence A. Quilliam,
Lawrence A. Quilliam
2Department of Biochemistry and Molecular Biology and Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN 46202
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Jonathan A. Cooper
Jonathan A. Cooper
1Fred Hutchinson Cancer Research Center, Seattle, WA 98109
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William T. Arthur
1Fred Hutchinson Cancer Research Center, Seattle, WA 98109
Lawrence A. Quilliam
2Department of Biochemistry and Molecular Biology and Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, IN 46202
Jonathan A. Cooper
1Fred Hutchinson Cancer Research Center, Seattle, WA 98109
Correspondence to William T. Arthur: [email protected]
Abbreviations used in this paper: CRD, cysteine-rich domain; DH, Dbl homology; GAP, GTPase activating protein; GBD, GTPase-binding domain; GEF, guanine nucleotide exchange factor; HV, hypervariable; PBD, p21-binding domain; PH, Pleckstrin homology; RBD POSH, Rac-binding domain of POSH; RBD Rhotekin, RhoA-binding domain of Rhotekin.
Received:
April 12 2004
Accepted:
August 25 2004
Online ISSN: 1540-8140
Print ISSN: 0021-9525
The Rockefeller University Press
2004
J Cell Biol (2004) 167 (1): 111–122.
Article history
Received:
April 12 2004
Accepted:
August 25 2004
Citation
William T. Arthur, Lawrence A. Quilliam, Jonathan A. Cooper; Rap1 promotes cell spreading by localizing Rac guanine nucleotide exchange factors . J Cell Biol 11 October 2004; 167 (1): 111–122. doi: https://doi.org/10.1083/jcb.200404068
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