Regulation of T cell receptor signaling by tyrosine phosphatase SYP association with CTLA-4.
The absence of CTLA-4 results in uncontrolled T cell proliferation. The T cell receptor-specific kinases FYN, LCK, and ZAP-70 as well as the RAS pathway were found to be activated in T cells of Ctla-4-/- mutant mice. In addition, CTLA-4 specifically associated with the tyrosine phosphatase SYP, an interaction mediated by the SRC homology 2 (SH2) domains of SYP and the phosphotyrosine sequence Tyr-Val-Lys-Met within the CTLA-4 cytoplasmic tail. The CTLA-4-associated SYP had phosphatase activity toward the RAS regulator p52SHC. Thus, the RAS pathway and T cell activation through the T cell receptor are regulated by CTLA-4-associated SYP.
Marengère
L E
LE
AMGEN Institute, Toronto, Ontario, Canada.
Waterhouse
P
P
Duncan
G S
GS
Mittrücker
H W
HW
Feng
G S
GS
Mak
T W
TW
D000069594:Abatacept; D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D060908:CTLA-4 Antigen; D051380:GRB2 Adaptor Protein; D018796:Immunoconjugates; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D015703:Antigens, CD; D000943:Antigens, Differentiation; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D051380:GRB2 Adaptor Protein; C495949:Grb2 protein, mouse; D018796:Immunoconjugates; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D011947:Receptors, Antigen, B-Cell; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D000069594:Abatacept; D011505:Protein-Tyrosine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D018631:ras Proteins