Abstract
Abstract Cbl, an E3 ubiquitin ligase, negatively regulates signal transduction events involved in thymic development. Most recently, we reported that inactivation of Cbl rescues the defect of T cell development in mice expressing a mutant SLP-76 that lacks the ability to bind Vav. The defect in T cell development in these SLP-76 mutant mice is similar to that of Vav1 deficient mice, marked by a block at the DN3 stage. It was therefore possible that Cbl inactivation facilitates T cell development through a Vav signaling pathway independent of SLP-76. To assess this possibility, we generated Cbl-/-Vav1-/- double knockout mouse and hypothesized that Cbl inactivation would not be able to reverse the defects of T cell development in Vav1-/- mice. Unexpectedly, the inactivation of Cbl rescued T cell development of Vav1-/- mice. Rescued development in Cbl-/-Vav1-/- DP thymocytes is associated with enhanced tyrosine-phosphorylation of signaling molecules, including Vav2, PLC-gama1 and ERKs in response to TCR stimulation. Therefore, Cbl normally inhibits a T cell differentiation pathway which is independent of Vav-1. The role of Vav2 and other components of this pathway remain to be elucidated.
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