Involvement of Src-homology-2-domain-containing protein-tyrosine phosphatase 2 in T cell activation.
Activation of resting T lymphocytes by ligands to the complex of T cell antigen receptor (TCR) and CD3 is initiated by a series of critical tyrosine phosphorylation and dephosphorylation events. Protein-tyrosine kinases of the Syk, Src and Csk families and the CD45 protein-tyrosine phosphatase (PTPase) are known to be involved in these early biochemical reactions. We have found that one of the two T-cell-expressed SH2-domain-containing PTPases, SHPTP2, is rapidly phosphorylated on tyrosine upon addition of anti-CD3 mAbs. This response was absent in cells lacking the Src family kinase Lck. Concomitantly with tyrosine phosphorylation, SHPTP2 co-immunoprecipitated with two unphosphorylated cellular proteins; phosphatidylinositol 3-kinase p85 and Grb2. Binding of SHPTP2 to Grb2 occurred through the SH2 domain of Grb2, while the association between SHPTP2 and p85 seemed to be mediated through Grb2 as an intermediate. In addition, many other molecules associate with Grb2 and may thereby become juxtaposed to SHPTP2. Our results indicate that SHPTP2 participates actively at an early stage in TCR signaling and that its phosphorylation on tyrosine may direct a Grb2-dependent association with selected substrates.
Tailor
P
P
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, CA 92037, USA.
Jascur
T
T
Williams
S
S
von Willebrand
M
M
Couture
C
C
Mustelin
T
T
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D001665:Binding Sites; D017252:CD3 Complex / Q000378:metabolism; D002460:Cell Line; D051380:GRB2 Adaptor Protein; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D008969:Molecular Sequence Data; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D017252:CD3 Complex; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases; D054648:Protein Phosphatase 2; D017027:Protein Tyrosine Phosphatases