Editors' ChoiceCell Migration

Dephosphorylation Drives Psuedopod Dynamics

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Science Signaling  24 Apr 2012:
Vol. 5, Issue 221, pp. ec119
DOI: 10.1126/scisignal.2003155

Members of the SCAR [suppressor of cyclic adenosine monophosphate (AMP) receptor] and WAVE [Wiskott-Aldrich syndrome protein (WASP)–family verprolin-homologous protein] family of adaptor proteins are part of a multiprotein complex that promotes the extension of cellular projections, such as pseudopods, by recruiting and activating factors that drive actin polymerization. Several phosphorylation events unique to specific cell types in mammals have been reported to modulate the activity of SCAR/WAVE, but mechanisms of regulation that are shared with simpler eukaryotes, and therefore likely to be common to most cells and species, have not been described. Ura et al. demonstrate that the phosphorylation state of SCAR also controls pseudopod dynamics during chemotaxis in the slime mold Dictyostelium discoideum. In both resting and chemotaxing cells, most (~98%) of the endogenous SCAR was phosphorylated at four serine residues in the C-terminal acidic region. To investigate the role of phosphorylation on SCAR activity, the authors used a nonphosphorylatable form of SCAR (SA SCAR) in which these serine residues were mutated to alanines and a phosphomimetic form of SCAR (SD SCAR) in which the serines were replaced with aspartate residues. Dictyostelium lacking scar polarized and migrated, but they were smaller than wild-type cells and migrated more slowly. Expression of a transgene encoding wild-type SCAR or SA SCAR fully rescued the scar mutant phenotype, and SD SCAR partially rescued it. Both SA SCAR and SD SCAR partially rescued migration speed but had opposite effects on pseudopod dynamics. Mutant cells rescued with SA SCAR were polarized and had large pseudopods that did not split; mutants rescued with SD SCAR were unpolarized and had small pseudopods that split abnormally. Wild-type SCAR complexes transiently accumulated in patches in pseudopod tips of migrating cells, but complexes containing SA SCAR accumulated in larger patches that persisted longer in the pseudopod tips, and complexes containing SD SCAR showed the opposite effect, with patches accumulating for less time. The persistence of SA SCAR at the pseudopod tip suggests that this form of SCAR might drive more actin polymerization than wild-type or SD SCAR, and the authors propose that SA SCAR is hyperactive. Furthermore, SA SCAR was rapidly degraded, suggesting a model in which dephosphorylation of basally phosphorylated SCAR leads to increased SCAR activity at the tips of pseudopods, which is rapidly degraded to drive pseudopod dynamics.

S. Ura, A. Y. Pollitt, D. M. Veltman, N. A. Morrice, L. M. Machesky, R. H. Insall, Pseudopod growth and evolution during cell movement is controlled through SCAR/WAVE dephosphorylation. Curr. Biol. 22, 553–561 (2012). [PubMed]

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