title: The SLP-76 Src homology 2 domain is required for T cell development and activation.
abstract: The adapter protein Src homology 2 (SH2) domain-containing leukocyte protein of 76 kDa (SLP-76) is critical for multiple aspects of T cell development and function. Through its protein-binding domains, SLP-76 serves as a platform for the assembly of multiple enzymes and adapter proteins that function together to activate second messengers required for TCR signal propagation. The N terminus of SLP-76, which contains three tyrosines that serve as docking sites for SH2 domain-containing proteins, and the central proline-rich region of SLP-76 have been well studied and are known to be important for both thymocyte selection and activation of peripheral T cells. Less is known about the function of the C-terminal SH2 domain of SLP-76. This region inducibly associates with ADAP and HPK1. Combining regulated deletion of endogenous SLP-76 with transgenic expression of a SLP-76 SH2 domain mutant, we demonstrate that the SLP-76 SH2 domain is required for peripheral T cell activation and positive selection of thymocytes, a function not previously attributed to this region. This domain is also important for T cell proliferation, IL-2 production, and phosphorylation of protein kinase D and IκB. ADAP-deficient T cells display similar, but in some cases less severe, defects despite phosphorylation of a negative regulatory site on SLP-76 by HPK1, a function that is lost in SLP-76 SH2 domain mutant T cells.
authors.affiliation: Department of Cancer Biology, Signal Transduction Program, Abramson Family Cancer Research Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Burns
authors.forename: Evann
authors.initials: E
authors.lastname: Corbo
authors.forename: Janine
authors.initials: J
authors.lastname: Degen
authors.forename: Mercy
authors.initials: M
authors.lastname: Gohil
authors.forename: Christine
authors.initials: C
authors.lastname: Anterasian
authors.forename: Burkart
authors.initials: B
authors.lastname: Schraven
authors.forename: Gary A
authors.initials: GA
authors.lastname: Koretzky
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kliche
authors.forename: Martha S
authors.initials: MS
authors.lastname: Jordan
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D018909:src Homology Domains / Q000235:genetics / Q000276:immunology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins