The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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© The Rockefeller University Press, 0022-1007/1998/5/1417/ $5.00
The Journal of Experimental Medicine, Volume 187, Number 9, May 4, 1998 1417-1426

Articles

The Phosphotyrosine Phosphatase SHP-2 Participates in a Multimeric Signaling Complex and Regulates T Cell Receptor (TCR) coupling to the Ras/Mitogen-activated Protein Kinase (MAPK) Pathway in Jurkat T Cells

Julie A. Frearson and Denis R. Alexander

From the T Cell Laboratory, Department of Immunology, The Babraham Institute, Cambridge, CB2 4AT, United Kingdom

Src homology 2 (SH2) domain–containing phosphotyrosine phosphatases (SHPs) are increasingly being shown to play critical roles in protein tyrosine kinase–mediated signaling pathways. The role of SHP-1 as a negative regulator of T cell receptor (TCR) signaling has been established. To further explore the function of the other member of this family, SHP-2, in TCR-mediated events, a catalytically inactive mutant SHP-2 was expressed under an inducible promoter in Jurkat T cells. Expression of the mutant phosphatase significantly inhibited TCR-induced activation of the extracellular-regulated kinase (ERK)-2 member of the mitogen-activated protein kinase (MAPK) family, but had no effect on TCR-{zeta} chain tyrosine phosphorylation or TCR-elicited Ca2+ transients. Inactive SHP-2 was targeted to membranes resulting in the selective increase in tyrosine phosphorylation of three membrane-associated candidate SHP-2 substrates of 110 kD, 55-60 kD, and 36 kD, respectively. Analysis of immunoprecipitates containing inactive SHP-2 also indicated that the 110-kD and 36-kD Grb-2–associated proteins were putative substrates for SHP-2. TCR-stimulation of Jurkat T cells expressing wild-type SHP-2 resulted in the formation of a multimeric cytosolic complex composed of SHP-2, Grb-2, phosphatidylinositol (PI) 3'-kinase, and p110. A significant proportion of this complex was shown to be membrane associated, presumably as a result of translocation from the cytosol. Catalytically inactive SHP-2, rather than the wild-type PTPase, was preferentially localized in complex with Grb-2 and the p85 subunit of PI 3'-kinase, suggesting that the dephosphorylating actions of SHP-2 may regulate the association of these signaling molecules to the p110 complex. Our results show that SHP-2 plays a critical role in linking the TCR to the Ras/MAPK pathway in Jurkat T cells, and also provide some insight into the molecular interactions of SHP-2 that form the basis of this signal transduction process.

Address correspondence to Dr. Denis R. Alexander, T Cell Laboratory, Department of Immunology, The Babraham Institute, Cambridge, CB2 4AT, UK. Phone: 01223-832312; Fax: 01223-837952; E-mail: denis.alexander{at}bbsrc.ac.uk

Abbreviations used: AEBSF, 4-(2-Aminoethyl)-benzenesulfonylfluoride.HCl; csw, corkscrew; ERK, extracellular regulated kinase; GST, glutathione s-transferase; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; PI, phosphatidylinositol; PTPase, phosphotyrosine phosphatase; SH2, Src homology 2; SHP, phosphotyrosine phosphatase.


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