Functional hierarchy of the N-terminal tyrosines of SLP-76.
The adaptor protein Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) plays a central role in T cell activation and T cell development. SLP-76 has three functional modules: an acidic domain with three key tyrosines, a central proline-rich domain, and a C-terminal Src homology 2 domain. Of these, mutation of the three N-terminal tyrosines (Y112, Y128, and Y145) results in the most profound effects on T cell development and function. Y112 and Y128 associate with Vav and Nck, two proteins shown to be important for TCR-induced phosphorylation of proximal signaling substrates, Ca(2+) flux, and actin reorganization. Y145 has been shown to be important for optimal association of SLP-76 with inducible tyrosine kinase, a key regulator of T cell function. To investigate further the role of the phosphorylatable tyrosines of SLP-76 in TCR signaling, cell lines and primary T cells expressing SLP-76 with mutations in individual or paired tyrosine residues were analyzed. These studies show that Tyr(145) of SLP-76 is the most critical tyrosine for both T cell function in vitro and T cell development in vivo.
Jordan
Martha S
MS
Signal Transduction Program, Leonard and Madlyn Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Sadler
Jeffrey
J
Austin
Jessica E
JE
Finkelstein
Lisa D
LD
Singer
Andrew L
AL
Schwartzberg
Pamela L
PL
Koretzky
Gary A
GA
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation / Q000235:genetics; D050778:NFATC Transcription Factors / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019000:Phosphotyrosine / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D050778:NFATC Transcription Factors; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C092947:SLP-76 signal Transducing adaptor proteins; D020703:ras GTPase-Activating Proteins; D019000:Phosphotyrosine; D014443:Tyrosine; D020928:Mitogen-Activated Protein Kinases; D051966:Phospholipase C gamma; D002118:Calcium