Cutting edge: rescue of pre-TCR but not mature TCR signaling in mice expressing membrane-targeted SLP-76.
SLP-76 (Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa) organizes signaling from immunoreceptors, including the platelet collagen receptor, the pre-TCR, and the TCR, and is required for T cell development. In this study we examine a mouse in which wild-type SLP-76 is replaced with a mutant constitutively targeted to the cell membrane. Membrane-targeted SLP-76 (MTS) supports ITAM signaling in platelets and from the pre-TCR. Signaling from the mature TCR, however, is defective in MTS thymocytes, resulting in failed T cell differentiation. Defective thymic selection by MTS is not rescued by a SLP-76 mutant whose localization is restricted to the cytosol. Thus, fixed localization of SLP-76 reveals differential requirements for the subcellular localization of signaling complexes downstream of the pre-TCR vs mature TCR.
Bezman
Natalie A
NA
Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
Baker
Rebecca G
RG
Lenox
Laurie E
LE
Jordan
Martha S
MS
Koretzky
Gary A
GA
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002462:Cell Membrane / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D018390:Gene Targeting; D006801:Humans; D019169:Jurkat Cells; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D011498:Protein Precursors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C110810:LAT protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D010750:Phosphoproteins; D011498:Protein Precursors; D016693:Receptors, Antigen, T-Cell, alpha-beta; C092947:SLP-76 signal Transducing adaptor proteins; C090377:pre-T cell receptor alpha