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A more recent version of this article appeared on June 1, 2004
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Submitted on February 21, 2004
Accepted on March 17, 2004
1 Cell Signaling and Developmental Biology Laboratory, Department of Biological Sciences, The National University of Singapore, 14 Science Drive 4, Singapore 117543, The Republic of Singapore
* Corresponding author. E-mail address: dbslowbc{at}nus.edu.sg.
Rho GTPases control cell dynamics during growth and development. They are activated by guanine nucleotide exchange factors and inactivated by GTPase-Activating Proteins (GAPs). Many GAPs exist with various protein modules, the functions of which largely remain unknown. We recently cloned and identified BPGAP1 as a novel RhoGAP that coordinately regulates pseudopodia and cell migration via the interplay of its BNIP-2 and Cdc42GAP Homology, RhoGAP and the proline-rich domains. To further elucidate the molecular mechanism underlying cell dynamics control by BPGAP1, we used protein precipitations and matrix-assisted laser desorption/ionization mass spectrometry and identified cortactin, a cortical actin binding protein as a novel partner of BPGAP1 both in vitro and in vivo. Progressive deletion studies confirmed that cortactin interacted directly and constitutively with the proline-rich motif 182-PPPRPPLP-189 of BPGAP1 via its Src Homology-3 domain. Together, they colocalized to periphery and enhanced cell migration. Furthermore, substitution of prolines at 184 and 186 with alanines completely abolished their interaction. Consequently, this BPGAP1 mutant failed to facilitate translocation of cortactin to the periphery and no enhanced cell migration was observed. These results provide the first evidence that a RhoGAP functionally interacts with cortactin and represents a novel determinant in the regulation of cell dynamics.
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