TY - JOUR
T1 - The carboxy-terminal region of CD5 is required for c-CBL mediated TCR signaling downmodulation in thymocytes
AU - Roa, Nelly S.
AU - Ordoñez-Rueda, Diana
AU - Chávez-Rios, Jesús R.
AU - Raman, Chander
AU - García-Zepeda, Eduardo A.
AU - Lozano, Francisco
AU - Soldevila, Gloria
PY - 2013/3/1
Y1 - 2013/3/1
N2 - 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.
AB - 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.
KW - C-Cbl
KW - CD5
KW - Downmodulation
KW - TCR
KW - Thymocyte
UR - http://www.scopus.com/inward/record.url?scp=84875371177&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2013.01.086
DO - 10.1016/j.bbrc.2013.01.086
M3 - Article
C2 - 23376399
AN - SCOPUS:84875371177
SN - 0006-291X
VL - 432
SP - 52
EP - 59
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -