FRL, a novel formin-related protein, binds to Rac and regulates cell motility and survival of macrophages.
We have isolated a cDNA, frl (formin-related gene in leukocytes), a novel mammalian member of the formin gene family. The frl cDNA encodes a 160-kDa protein, FRL, that possesses FH1, FH2, and FH3 domains that are well conserved among other Formin-related proteins. An FRL protein is mainly localized in the cytosol and is highly expressed in spleen, lymph node, and bone marrow cells. Formin-related genes and proteins have been reported to play crucial roles in morphogenesis, cell polarity, and cytokinesis through interaction with Rho family small GTPases. FRL binds to Rac at its N-terminal region including the FH3 domain and associates with profilin at the FH1 domain. In a macrophage cell line, P388D1, overexpression of a truncated form of FRL containing only the FH3 domain (FH3-FRL) strongly inhibited cell adhesion to fibronectin and migration upon stimulation with a chemokine. Moreover, expression of the truncated FH3-FRL protein resulted in apoptotic cell death of P388D1 cells, suggesting that the truncated FH3-FRL protein may interfere with signals of FRL. Overexpression in the P388D1 cells of full-length FRL or of the truncated protein containing the FH3 and FH1 domains, with simultaneous expression of the truncated FH3-FRL protein, blocked apoptotic cell death and inhibition of cell adhesion and migration. These results suggest that FRL may play a role in the control of reorganization of the actin cytoskeleton in association with Rac and also in the regulation of the signal for cell survival.
Yayoshi-Yamamoto
S
S
Department of Molecular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Taniuchi
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I
Watanabe
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T
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D019556:COS Cells; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D002470:Cell Survival; D002633:Chemotaxis; D003285:Contractile Proteins; D018076:DNA, Complementary; D015870:Gene Expression; D007424:Intracellular Fluid / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D051304:Profilins; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011817:Rabbits; D017384:Sequence Deletion; D014018:Tissue Distribution; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D003285:Contractile Proteins; D018076:DNA, Complementary; D008840:Microfilament Proteins; C495739:Pfn1 protein, mouse; D051304:Profilins; D011506:Proteins; D020830:rac1 GTP-Binding Protein