. The c-Cbl proto- oncogene product is tyrosine-phosphorylated upon stimulation of a wide range of receptors, including the T-cell antigen receptor (TCR). Both Fyn and ZAP-70 contribute to the phosphorylation of Cbl in T cells, and the tyrosine phosphorylation of Cbl induces its interaction with a number of important signaling molecules, including Grb2, PI 3-kinase, CrkL, and 14-3-3 proteins. However, whether Cbl plays a positive or a negative role in signal transduction through the TCR remains unclear. The applicant proposes that abnormal Cbl phosphorylation and function contributes to the pathogenesis of certain autoimmune diseases, a relevant example being the syndrome manifested by the autoimmune nonobese diabetic (NOD) mouse.
The specific aims of this proposal are: (1) to define the interactions between the Fyn and ZAP-70 tyrosine kinases and Cbl, (2) to define the downstream targets of Cbl in activated T cells, and (3) to determine whether altered Cbl function contributes to the hypo-responsive status of T cells in NOD mice.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056558-04
Application #
6517658
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Akolkar, Beena
Project Start
1999-05-01
Project End
2003-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
4
Fiscal Year
2002
Total Cost
$240,292
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Liu, Yun-Cai (2004) Ubiquitin ligases and the immune response. Annu Rev Immunol 22:81-127
Shao, Yuan; Yang, Chun; Elly, Chris et al. (2004) Differential regulation of the B cell receptor-mediated signaling by the E3 ubiquitin ligase Cbl. J Biol Chem 279:43646-53
Shao, Yuan; Elly, Chris; Liu, Yun-Cai (2003) Negative regulation of Rap1 activation by the Cbl E3 ubiquitin ligase. EMBO Rep 4:425-31
Zhang, Wenying; Shao, Yuan; Fang, Deyu et al. (2003) Negative regulation of T cell antigen receptor-mediated Crk-L-C3G signaling and cell adhesion by Cbl-b. J Biol Chem 278:23978-83
Fang, Deyu; Elly, Chris; Gao, Baixue et al. (2002) Dysregulation of T lymphocyte function in itchy mice: a role for Itch in TH2 differentiation. Nat Immunol 3:281-7
Fang, D; Wang, H Y; Fang, N et al. (2001) Cbl-b, a RING-type E3 ubiquitin ligase, targets phosphatidylinositol 3-kinase for ubiquitination in T cells. J Biol Chem 276:4872-8
Fang, D; Liu, Y C (2001) Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nat Immunol 2:870-5
Qiu, L; Joazeiro, C; Fang, N et al. (2000) Recognition and ubiquitination of Notch by Itch, a hect-type E3 ubiquitin ligase. J Biol Chem 275:35734-7
Joazeiro, C A; Wing, S S; Huang, H et al. (1999) The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science 286:309-12