title: Bi-modal regulation of a formin by srGAP2.
abstract: The maintenance of rapid and efficient actin dynamics in vivo requires coordination of filament assembly and disassembly. This regulation requires temporal and spatial integration of signaling pathways by protein complexes. However, it remains unclear how these complexes form and then regulate the actin cytoskeleton. Here, we identify a srGAP2 and formin-like 1 (FMNL1, also known as FRL1 or FRLα) complex whose assembly is regulated by Rac signaling. Our data suggest srGAP2 regulates FMNL1 in two ways; 1) Rac-mediated activation of FMNL1 leads to the recruitment of srGAP2, which contains a Rac-specific GAP domain; 2) the SH3 domain of srGAP2 binds the formin homology 1 domain of FMNL1 to inhibit FMNL1-mediated actin severing. Thus, srGAP2 can efficiently terminate the upstream activating Rac signal while also opposing an important functional output of FMNL1, namely actin severing. We also show that FMNL1 and srGAP2 localize to the actin-rich phagocytic cup of macrophage-derived cells, suggesting the complex may regulate this Rac- and actin-driven process in vivo. We propose that after Rac-dependent activation of FMNL1, srGAP2 mediates a potent mechanism to limit the duration of Rac action and inhibit formin activity during rapid actin dynamics.
authors.affiliation: Department of Cell Biology, Duke University Medical School, Durham, North Carolina 27710, USA.
authors.forename: Frank M
authors.initials: FM
authors.lastname: Mason
authors.forename: Ernest G
authors.initials: EG
authors.lastname: Heimsath
authors.forename: Henry N
authors.initials: HN
authors.lastname: Higgs
authors.forename: Scott H
authors.initials: SH
authors.lastname: Soderling
mesh_terms: D000199:Actins; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D000080865:Formins; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D010588:Phagosomes / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D018909:src Homology Domains
chemical_list: D000199:Actins; D003598:Cytoskeletal Proteins; C476204:FMNL1 protein, human; D000080865:Formins; D020690:GTPase-Activating Proteins; D046912:Multiprotein Complexes; C501995:SRGAP2 protein, human; D051057:Proto-Oncogene Proteins c-akt