title: The carboxy-terminal region of CD5 is required for c-CBL mediated TCR signaling downmodulation in thymocytes.
abstract: CD5 functions as a negative regulator of TCR signaling during thymocyte development, however, the molecular mechanisms involved in this process remain elusive. A key molecule involved in the down modulation of TCR signaling is c-Cbl, an ubiquitin ligase that physically associates with CD5. Crosslinking of TCR in thymocytes leads to ubiquitylation and lysosomal/proteasomal degradation of TCR downstream signaling effectors and CD5 itself. The present report shows that co-engagement of CD3 with CD5 enhanced c-Cbl phosphorylation, which was not affected by the deletion of the pseudo-ITAM domain of CD5, the putative binding site for c-Cbl. However, amino acids present in the carboxy-terminal region of CD5, were necessary for this effect, indicating that ITAM-independent sites were involved in the interaction of c-Cbl with CD5. The carboxy-terminal region of CD5 was also required for Vav degradation, a well-known target for c-Cbl-dependent ubiquitylation. These results support the notion that the distal cytoplasmic domain of CD5, including Y463, plays a relevant role in the downmodulation of TCR signals in thymocytes via c-Cbl.
authors: Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, México, DF 04510, Mexico.
authors: Nelly S
authors: NS
authors: Roa
authors: Diana
authors: D
authors: Ordoñez-Rueda
authors: Jesús R
authors: JR
authors: Chávez-Rios
authors: Chander
authors: C
authors: Raman
authors: Eduardo A
authors: EA
authors: García-Zepeda
authors: Francisco
authors: F
authors: Lozano
authors: Gloria
authors: G
authors: Soldevila
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018956:CD5 Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D017384:Sequence Deletion; D015398:Signal Transduction; D060168:Thymocytes / Q000378:metabolism*
chemical_list: D018956:CD5 Antigens; C526836:Cd5 protein, mouse; D011948:Receptors, Antigen, T-Cell; D050721:Proto-Oncogene Proteins c-cbl; C493849:Cbl protein, mouse