Volume 272, Number 2, Issue of January 10, 1997 pp. 894-902
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

---

The Role of a Lymphoid-restricted, Grb2-like SH3-SH2-SH3 Protein in T Cell Receptor Signaling

(Received for publication, September 20, 1996)

Thomas Trüb ^§ , J. Daniel Frantz ^§ , Masaya Miyazaki ^§ , Hamid Band ^§** and Steven E. Shoelson ^§

From the  Research Division, Joslin Diabetes Center, the ^** Lymphocyte Biology Section, Division of Rheumatology and Immunology, and ^§ Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215

We have characterized an SH3-SH2-SH3 linker protein that is prominently expressed in lymphoid tissues. This protein has 58% sequence identity to Grb2. An identical protein called Grap has been found in hematopoietic cells. In Jurkat cells, T cell receptor activation leads to the association of Grap with phosphoproteins p36/38 and, to a lesser degree, Shc. This interaction is mediated by the Grap SH2 domain, which has similar binding specificity to the Grb2 SH2 domain. Grap also associates via its SH3 domains with Sos, the Ras guanine nucleotide exchange factor; with dynamin, a GTPase involved in membrane protein trafficking; and with Sam68, a nuclear RNA-binding protein that serves as a substrate of Src kinases during mitosis. T cell activation effects an increase in Grap association with p36/38, Shc, Sos, and dynamin. Sam68 binding is constitutive. Phospholipase C-1 and Fyn are also found in activated Grap signaling complexes, although these interactions may not be direct. We conclude that Grap is a prominent component of lymphocyte receptor signaling. Based on the known functions of bound effector molecules, Grap-mediated responses to antigen challenge may include endocytosis of the T cell receptor, cellular proliferation, and regulated entry into the cell cycle.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				I. Isnardi, R. Lesourne, P. Bruhns, W. H. Fridman, J. C. Cambier, and M. Daeron Two Distinct Tyrosine-based Motifs Enable the Inhibitory Receptor Fc{gamma}RIIB to Cooperatively Recruit the Inositol Phosphatases SHIP1/2 and the Adapters Grb2/Grap J. Biol. Chem., December 10, 2004; 279(50): 51931 - 51938. [Abstract] [Full Text] [PDF]

				M. Itoh, I. Haga, Q.-H. Li, and J.-i. Fujisawa Identification of cellular mRNA targets for RNA-binding protein Sam68 Nucleic Acids Res., December 15, 2002; 30(24): 5452 - 5464. [Abstract] [Full Text] [PDF]

				R. Shen, Y.-B. Ouyang, C.-K. Qu, A. Alonso, L. Sperzel, T. Mustelin, M. H. Kaplan, and G.-S. Feng Grap Negatively Regulates T-Cell Receptor-Elicited Lymphocyte Proliferation and Interleukin-2 Induction Mol. Cell. Biol., May 15, 2002; 22(10): 3230 - 3236. [Abstract] [Full Text] [PDF]

				C. L. Sommers, R. K. Menon, A. Grinberg, W. Zhang, L. E. Samelson, and P. E. Love Knock-In Mutation of the Distal Four Tyrosines of Linker for Activation of T Cells Blocks Murine T Cell Development J. Exp. Med., July 9, 2001; 194(2): 135 - 142. [Abstract] [Full Text] [PDF]

				C. Gilbert, F. Barabe, E. Rollet-Labelle, S. G. Bourgoin, S. R. McColl, B. B. Damaj, and P. H. Naccache Evidence for a Role for SAM68 in the Responses of Human Neutrophils to Ligation of CD32 and to Monosodium Urate Crystals J. Immunol., April 1, 2001; 166(7): 4664 - 4671. [Abstract] [Full Text] [PDF]

				B. J. Irvin, B. L. Williams, A. E. Nilson, H. O. Maynor, and R. T. Abraham Pleiotropic Contributions of Phospholipase C-gamma 1 (PLC-gamma 1) to T-Cell Antigen Receptor-Mediated Signaling: Reconstitution Studies of a PLC-gamma 1-Deficient Jurkat T-Cell Line Mol. Cell. Biol., December 15, 2000; 20(24): 9149 - 9161. [Abstract] [Full Text]

				V. Sundvold, K. M. Torgersen, N. H. Post, F. Marti, P. D. King, J. A. Rottingen, A. Spurkland, and T. Lea Cutting Edge: T Cell-Specific Adapter Protein Inhibits T Cell Activation by Modulating Lck Activity J. Immunol., September 15, 2000; 165(6): 2927 - 2931. [Abstract] [Full Text] [PDF]

				J. J. Derry, S. Richard, H. Valderrama Carvajal, X. Ye, V. Vasioukhin, A. W. Cochrane, T. Chen, and A. L. Tyner Sik (BRK) Phosphorylates Sam68 in the Nucleus and Negatively Regulates Its RNA Binding Ability Mol. Cell. Biol., August 15, 2000; 20(16): 6114 - 6126. [Abstract] [Full Text]

				S. K. Liu, C. A. Smith, R. Arnold, F. Kiefer, and C. J. McGlade The Adaptor Protein Gads (Grb2-Related Adaptor Downstream of Shc) Is Implicated in Coupling Hemopoietic Progenitor Kinase-1 to the Activated TCR J. Immunol., August 1, 2000; 165(3): 1417 - 1426. [Abstract] [Full Text] [PDF]

				J. H. Ellis, C. Ashman, M. N. Burden, K. E. Kilpatrick, M. A. Morse, and P. A. Hamblin GRID: A Novel Grb-2-Related Adapter Protein That Interacts with the Activated T Cell Costimulatory Receptor CD28 J. Immunol., June 1, 2000; 164(11): 5805 - 5814. [Abstract] [Full Text] [PDF]

				S. I. Gringhuis, A. Leow, E. A. M. Papendrecht-van der Voort, P. H. J. Remans, F. C. Breedveld, and C. L. Verweij Displacement of Linker for Activation of T Cells from the Plasma Membrane Due to Redox Balance Alterations Results in Hyporesponsiveness of Synovial Fluid T Lymphocytes in Rheumatoid Arthritis J. Immunol., February 15, 2000; 164(4): 2170 - 2179. [Abstract] [Full Text] [PDF]

				J. Lin, A. Weiss, and T. S. Finco Localization of LAT in Glycolipid-enriched Microdomains Is Required for T cell Activation J. Biol. Chem., October 8, 1999; 274(41): 28861 - 28864. [Abstract] [Full Text] [PDF]

				V. Lang, M. Semichon, F. Michel, C. Brossard, H. Gary-Gouy, and G. Bismuth Fyn Membrane Localization Is Necessary to Induce the Constitutive Tyrosine Phosphorylation of Sam68 in the Nucleus of T Lymphocytes J. Immunol., June 15, 1999; 162(12): 7224 - 7232. [Abstract] [Full Text] [PDF]

				H. Asada, N. Ishii, Y. Sasaki, K. Endo, H. Kasai, N. Tanaka, T. Takeshita, S. Tsuchiya, T. Konno, and K. Sugamura Grf40, A Novel Grb2 Family Member, Is Involved in T Cell Signaling through Interaction with SLP-76 and LAT J. Exp. Med., May 3, 1999; 189(9): 1383 - 1390. [Abstract] [Full Text] [PDF]

				M. Huber, K. A. Watson, H.-C. Selinka, C. M. Carthy, K. Klingel, B. M. McManus, and R. Kandolf Cleavage of RasGAP and Phosphorylation of Mitogen-Activated Protein Kinase in the Course of Coxsackievirus B3 Replication J. Virol., May 1, 1999; 73(5): 3587 - 3594. [Abstract] [Full Text]

				S. L. Harmer and A. L. DeFranco The Src Homology Domain 2-Containing Inositol Phosphatase SHIP Forms a Ternary Complex with Shc and Grb2 in Antigen Receptor-stimulated B Lymphocytes J. Biol. Chem., April 23, 1999; 274(17): 12183 - 12191. [Abstract] [Full Text] [PDF]

				C.-L. Law, M. K. Ewings, P. M. Chaudhary, S. A. Solow, T. J. Yun, A. J. Marshall, L. Hood, and E. A. Clark GrpL, a Grb2-related Adaptor Protein, Interacts with SLP-76 to Regulate Nuclear Factor of Activated T Cell Activation J. Exp. Med., April 19, 1999; 189(8): 1243 - 1253. [Abstract] [Full Text] [PDF]

				M. Di Fruscio, T. Chen, and S. Richard Characterization of Sam68-like mammalian proteins SLM-1 and SLM-2: SLM-1 is a Src substrate during mitosis PNAS, March 16, 1999; 96(6): 2710 - 2715. [Abstract] [Full Text] [PDF]

				A. Hashimoto, H. Okada, A. Jiang, M. Kurosaki, S. Greenberg, E. A. Clark, and T. Kurosaki Involvement of Guanosine Triphosphatases and Phospholipase C-gamma 2 in Extracellular Signal-regulated Kinase, c-Jun NH2-terminal Kinase, and p38 Mitogen-activated Protein Kinase Activation by the B Cell Antigen Receptor J. Exp. Med., October 5, 1998; 188(7): 1287 - 1295. [Abstract] [Full Text] [PDF]

				J. Wong, M. Ishiai, T. Kurosaki, and A. C. Chan Functional Complementation of BLNK by SLP-76 and LAT Linker Proteins J. Biol. Chem., October 13, 2000; 275(42): 33116 - 33122. [Abstract] [Full Text] [PDF]

				K. Liu, L. Li, P. E. Nisson, C. Gruber, J. Jessee, and S. N. Cohen Neoplastic Transformation and Tumorigenesis Associated with Sam68 Protein Deficiency in Cultured Murine Fibroblasts J. Biol. Chem., December 15, 2000; 275(51): 40195 - 40201. [Abstract] [Full Text] [PDF]