Article thumbnail

Cbl Enforces Vav1 Dependence and a Restricted Pathway of T Cell Development

By Jeffrey Chiang and Richard J. Hodes


Extensive studies of pre-TCR- and TCR-dependent signaling have led to characterization of a pathway deemed essential for efficient T cell development, and comprised of a cascade of sequential events involving phosphorylation of Lck and ZAP-70, followed by phosphorylation of LAT and SLP-76, and subsequent additional downstream events. Of interest, however, reports from our lab as well as others have indicated that the requirements for ZAP-70, LAT, and SLP-76 are partially reversed by inactivation of c-Cbl (Cbl), an E3 ubiquitin ligase that targets multiple molecules for ubiquitination and degradation. Analysis of signaling events in these Cbl knockout models, including the recently reported analysis of SLP-76 transgenes defective in interaction with Vav1, suggested that activation of Vav1 might be a critical event in alternative pathways of T cell development. To extend the analysis of signaling requirements for thymic development, we have therefore assessed the effect of Cbl inactivation on the T cell developmental defects that occur in Vav1-deficient mice. The defects in Vav1-deficient thymic development, including a marked defect in DN3-DN4 transition, were completely reversed by Cbl inactivation, accompanied by enhanced phosphorylation of PLC-γ1 and ERKs in response to pre-TCR/TCR cross-linking of Vav1-/-Cbl-/- DP thymocytes. Taken together, these results suggest a substantially modified paradigm for pre-TCR/TCR signaling and T cell development. The observed consensus pathways of T cell development, including requirements for ZAP-70, LAT, SLP-76, and Vav1, appear to reflect the restriction by Cbl of an otherwise much broader set of molecular pathways capable of mediating T cell development

Topics: Research Article
Publisher: Public Library of Science
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. (2003). A mouse with a loss-of-function mutation in the c-Cbl TKB domain shows perturbed thymocyte signaling without enhancing the activity of the ZAP70 tyrosine kinase.
  2. (1997). A requirement for the Rho-family GTP exchange factor Vav in positive and negative selection of thymocytes.
  3. (2008). A tale of two Cbls: interplay of c-Cbl and Cbl-b in epidermal growth factor receptor downregulation.
  4. (1998). Altered thymic positive selection and intracellular signals in Cbl-deficient mice.
  5. (2007). August A
  6. (2005). c-Cbl and Cbl-b ubiquitin ligases: substrate diversity and the negative regulation of signalling responses.
  7. (2009). Cbl enforces an SLP76-dependent signaling pathway for T cell differentiation.
  8. (2000). Cbl-b is a negative regulator of receptor clustering and raft aggregation in T cells.
  9. (2003). Cblmediated ubiquitinylation and negative regulation of Vav.
  10. (2001). Differential requirement for SLP-76 domains in T cell development and function.
  11. (1998). Differential requirements for ZAP-70 in TCR signaling and T cell development.
  12. (1997). Direct T cell activation by chimeric single chain Fv-Syk promotes Syk-Cbl association and Cbl phosphorylation.
  13. (2005). Fetal expression of Fas ligand is necessary and sufficient for induction of CD8 T cell tolerance to the fetal antigen H-Y during pregnancy.
  14. (1998). Impaired viability and profound block in thymocyte development in mice lacking the adaptor protein SLP-76.
  15. (2004). Inactivation of c-Cbl reverses neonatal lethality and T cell developmental arrest of SLP-76-deficient mice.
  16. (1996). Interactions of Cbl with two adapter proteins,
  17. (1996). p120cbl is a major substrate of tyrosine phosphorylation upon B cell antigen receptor stimulation and interacts
  18. (1999). Perturbed regulation of ZAP-70 and sustained tyrosine phosphorylation of LAT and SLP-76 in c-Cbl-deficient thymocytes.
  19. (2009). Regulation of lymphocyte development and activation by the LAT family of adapter proteins.
  20. (1998). Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development.
  21. (2006). Src-like adaptor protein regulates TCR expression on thymocytes by linking the ubiquitin ligase c-Cbl to the TCR complex.
  22. (2004). The SLP-76 family of adapter proteins.
  23. (2009). The structure, regulation, and function of ZAP-70.
  24. (2002). Vav1 transduces T cell receptor signals to the activation of phospholipase Cgamma1 via phosphoinositide 3-kinase-dependent and -independent pathways.
  25. (2004). Vav1 transduces T cell receptor signals to the activation of the Ras/ERK pathway via LAT, Sos, and RasGRP1.
  26. (2003). Vav1/2/3-null mice define an essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells.
  27. (2005). Weiss A