Identification of two signaling submodules within the CrkII/ELMO/Dock180 pathway regulating engulfment of apoptotic cells.

Tosello-Trampont, A-C; Kinchen, J M; Brugnera, E; Haney, L B; Hengartner, M O; Ravichandran, K S

Tosello-Trampont, A-C; Kinchen, J M; Brugnera, E; Haney, L B; Hengartner, M O; Ravichandran, K S.

Afiliación

Tosello-Trampont AC; Beirne Carter Center for Immunology Research and the Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.

Cell Death Differ ; 14(5): 963-72, 2007 May.

Article en En | MEDLINE | ID: mdl-17304244

RESUMEN

Removal of apoptotic cells is a dynamic process coordinated by ligands on apoptotic cells, and receptors and other signaling proteins on the phagocyte. One of the fundamental challenges is to understand how different phagocyte proteins form specific and functional complexes to orchestrate the recognition/removal of apoptotic cells. One evolutionarily conserved pathway involves the proteins cell death abnormal (CED)-2/chicken tumor virus no. 10 (CT10) regulator of kinase (Crk)II, CED-5/180 kDa protein downstream of chicken tumor virus no. 10 (Crk) (Dock180), CED-12/engulfment and migration (ELMO) and MIG-2/RhoG, leading to activation of the small GTPase CED-10/Rac and cytoskeletal remodeling to promote corpse uptake. Although the role of ELMO : Dock180 in regulating Rac activation has been well defined, the function of CED-2/CrkII in this complex is less well understood. Here, using functional studies in cell lines, we observe that a direct interaction between CrkII and Dock180 is not required for efficient removal of apoptotic cells. Similarly, mutants of CED-5 lacking the CED-2 interaction motifs could rescue engulfment and migration defects in CED-5 deficient worms. Mutants of CrkII and Dock180 that could not biochemically interact could colocalize in membrane ruffles. Finally, we identify MIG-2/RhoG (which functions upstream of Dock180 : ELMO) as a possible point of crosstalk between these two signaling modules. Taken together, these data suggest that Dock180/ELMO and CrkII act as two evolutionarily conserved signaling submodules that coordinately regulate engulfment.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/metabolismo; Apoptosis; Caenorhabditis elegans/citología; Fagocitosis; Proteínas Proto-Oncogénicas c-crk/metabolismo; Transducción de Señal; Proteínas de Unión al GTP rac/metabolismo; Animales; Sitios de Unión; Caenorhabditis elegans/metabolismo; Proteínas de Caenorhabditis elegans/metabolismo; Movimiento Celular; Pollos/virología; Células HeLa; Humanos; Proteínas de la Membrana/metabolismo; Ratones; Células 3T3 NIH; Unión Proteica; Estructura Terciaria de Proteína; Transporte de Proteínas; Proteínas de Unión al GTP rho/metabolismo

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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Fagocitosis / Transducción de Señal / Caenorhabditis elegans / Apoptosis / Proteínas de Unión al GTP rac / Proteínas Adaptadoras Transductoras de Señales / Proteínas Proto-Oncogénicas c-crk Tipo de estudio: Diagnostic_studies Límite: Animals / Humans Idioma: En Revista: Cell Death Differ Año: 2007 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido

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