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Science 18 April 1997:
Vol. 276. no. 5311, pp. 418 - 420
DOI: 10.1126/science.276.5311.418
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Reports

The Product of the Proto-Oncogene c-cbl: A Negative Regulator of the Syk Tyrosine Kinase

Yasuo Ota, Lawrence E. Samelson *

Engagement of antigen and immunoglobulin receptors on hematopoietic cells is directly coupled to activation of nonreceptor protein tyrosine kinases (PTKs) that then phosphorylate critical intracellular substrates. In mast cells stimulated through the Fcepsilon RI receptor, activation of several PTKs including Syk leads to degranulation and release of such mediators of the allergic response as histamine and serotonin. Regulation of Syk function occurred through interaction with the Cbl protein, itself a PTK substrate in this system. Overexpression of Cbl led to inhibition of Syk and suppression of serotonin release from mast cells, demonstrating its ability to inhibit a nonreceptor tyrosine kinase. Complex adaptor proteins such as Cbl can directly regulate the functions of the proteins they bind.

Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-5430, USA.
*   To whom correspondence should be addressed. E-mail: samelson{at}helix.nih.gov

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Interleukin-2 Stimulation Induces Tyrosine Phosphorylation of p120-Cbl and CrkL and Formation of Multimolecular Signaling Complexes in T Lymphocytes and Natural Killer Cells.
F. Gesbert, C. Garbay, and J. Bertoglio (1998)
J. Biol. Chem. 273, 3986-3993
   Abstract »    Full Text »    PDF »
Regulation of Interferon-Induced Protein Kinase PKR: Modulation of P58IPK Inhibitory Function by a Novel Protein, P52rIPK.
M. Gale Jr., C. M. Blakely, D. A. Hopkins, M. W. Melville, M. Wambach, P. R. Romano, and M. G. Katze (1998)
Mol. Cell. Biol. 18, 859-871
   Abstract »    Full Text »
The Cbl Phosphotyrosine-binding Domain Selects a D(N/D)XpY Motif and Binds to the Tyr292 Negative Regulatory Phosphorylation Site of ZAP-70.
M. L. Lupher Jr., Z. Songyang, S. E. Shoelson, L. C. Cantley, and H. Band (1997)
J. Biol. Chem. 272, 33140-33144
   Abstract »    Full Text »    PDF »
Cbl-mediated Regulation of T Cell Receptor-induced AP1 Activation. IMPLICATIONS FOR ACTIVATION VIA THE Ras SIGNALING PATHWAY.
B. L. Rellahan, L. J. Graham, B. Stoica, K. E. DeBell, and E. Bonvini (1997)
J. Biol. Chem. 272, 30806-30811
   Abstract »    Full Text »    PDF »
Impaired Plasma Membrane Targeting of Grb2-Murine Son of Sevenless (mSOS) Complex and Differential Activation of the Fyn-T Cell Receptor (TCR)-{zeta}-Cbl Pathway Mediate T Cell Hyporesponsiveness in Autoimmune Nonobese Diabetic Mice.
K. Salojin, J. Zhang, M. Cameron, B. Gill, G. Arreaza, A. Ochi, and T. L. Delovitch (1997)
J. Exp. Med. 186, 887-897
   Abstract »    Full Text »    PDF »
Evidence for Direct Interaction between Sprouty and Cbl.
E. S. M. Wong, J. Lim, B. C. Low, Q. Chen, and G. R. Guy (2001)
J. Biol. Chem. 276, 5866-5875
   Abstract »    Full Text »    PDF »
Vav2 Activates c-fos Serum Response Element and CD69 Expression but Negatively Regulates Nuclear Factor of Activated T Cells and Interleukin-2 Gene Activation in T Lymphocyte.
S. Tartare-Deckert, M.-N. Monthouel, C. Charvet, I. Foucault, E. Van Obberghen, A. Bernard, A. Altman, and M. Deckert (2001)
J. Biol. Chem. 276, 20849-20857
   Abstract »    Full Text »    PDF »
Cbl Promotes Ubiquitination of the T Cell Receptor zeta through an Adaptor Function of Zap-70.
H.-Y. Wang, Y. Altman, D. Fang, C. Elly, Y. Dai, Y. Shao, and Y.-C. Liu (2001)
J. Biol. Chem. 276, 26004-26011
   Abstract »    Full Text »    PDF »
Potentiation of Insulin-related Signal Transduction by a Novel Protein-tyrosine Phosphatase Inhibitor, Et-3,4-dephostatin, on Cultured 3T3-L1 Adipocytes.
T. Suzuki, A. Hiroki, T. Watanabe, T. Yamashita, I. Takei, and K. Umezawa (2001)
J. Biol. Chem. 276, 27511-27518
   Abstract »    Full Text »    PDF »
T Cell Activation Induces Direct Binding of the Crk Adapter Protein to the Regulatory Subunit of Phosphatidylinositol 3-Kinase (p85) via a Complex Mechanism Involving the Cbl Protein.
S. Gelkop, Y. Babichev, and N. Isakov (2001)
J. Biol. Chem. 276, 36174-36182
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Src-catalyzed Phosphorylation of c-Cbl Leads to the Interdependent Ubiquitination of Both Proteins.
M. Yokouchi, T. Kondo, A. Sanjay, A. Houghton, A. Yoshimura, S. Komiya, H. Zhang, and R. Baron (2001)
J. Biol. Chem. 276, 35185-35193
   Abstract »    Full Text »    PDF »
Ubiquitination and degradation of Syk and ZAP-70 protein tyrosine kinases in human NK cells upon CD16 engagement.
R. Paolini, R. Molfetta, M. Piccoli, L. Frati, and A. Santoni (2001)
PNAS 98, 9611-9616
   Abstract »    Full Text »    PDF »


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