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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3648-3654. Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI 10.1182/blood-2004-10-3916. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-10-3916v1 105/9/3648    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zheng, Y. Articles by Stone, J. C. Search for Related Content PubMed PubMed Citation Articles by Zheng, Y. Articles by Stone, J. C. Related Collections Immunobiology Oncogenes and Tumor Suppressors Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells Yong Zheng, Huaizhi Liu, Jason Coughlin, Jing Zheng, Liang Li, and James C. Stone From the Departments of Biochemistry and Chemistry, University of Alberta, Edmonton, AB, Canada. B-cell receptor (BCR) signaling activates a number of intracellular signaling molecules including phospholipase C–2 (PLC-2), which generates membrane diacylglycerol (DAG). DAG recruits both protein kinase C (PKC) and RasGRP family members to the membrane and contributes to their activation. We have hypothesized that membrane colocalization facilitates activation of RasGRP3 by PKC. Here we demonstrate that PKC phosphorylates RasGRP3 on Thr133 in vitro, as determined by mass spectrometry. RasGRP3 with a Thr133Ala substitution is a poor PKC substrate in vitro and a poor Ras activator in vivo. Antiphosphopeptide antibodies recognize Thr133-phosphorylated RasGRP3 in B cells after BCR stimulation or DAG analog treatment, but much less so in resting cells. PKC inhibitors block RasGRP3 Thr133 phosphorylation and Ras–extracellular signal-related kinase (Erk) signaling with a similar pattern. After stimulation of T-cell receptor (TCR) or DAG analog treatment of T cells, PKC-catalyzed phosphorylation of RasGRP1 occurs on the homologous residue, Thr184. These studies shed light on the proposed "PKC-Ras pathway" and support the hypothesis that RasGRP phosphorylation by PKC is a mechanism that integrates DAG signaling systems in T and B cells. PKC-mediated regulation of RasGRPs in lymphocytes may generate cooperative signaling in response to increases in DAG. The mast- and myeloid-selective family member RasGRP4 is regulated by different means. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. J. Botelho, R. E. Harrison, J. C. Stone, J. F. Hancock, M. R. Philips, J. Jongstra-Bilen, D. Mason, J. Plumb, M. R. Gold, and S. Grinstein Localized Diacylglycerol-dependent Stimulation of Ras and Rap1 during Phagocytosis J. Biol. Chem., October 16, 2009; 284(42): 28522 - 28532. [Abstract] [Full Text] [PDF] Y. Imamura, A. Oda, T. Katahira, K. Bundo, K. A. Pike, M. J. H. Ratcliffe, and D. Kitamura BLNK Binds Active H-Ras to Promote B Cell Receptor-mediated Capping and ERK Activation J. Biol. Chem., April 10, 2009; 284(15): 9804 - 9813. [Abstract] [Full Text] [PDF] G. P. Katsoulotos, M. Qi, J. C. Qi, K. Tanaka, W. E. Hughes, T. J. Molloy, R. Adachi, R. L. Stevens, and S. A. Krilis The Diacylglycerol-dependent Translocation of Ras Guanine Nucleotide-releasing Protein 4 inside a Human Mast Cell Line Results in Substantial Phenotypic Changes, Including Expression of Interleukin 13 Receptor {alpha}2 J. Biol. Chem., January 18, 2008; 283(3): 1610 - 1621. [Abstract] [Full Text] [PDF] B. Ko, L. M. Joshi, L. L. Cooke, N. Vazquez, M. W. Musch, S. C. Hebert, G. Gamba, and R. S. Hoover Phorbol ester stimulation of RasGRP1 regulates the sodium-chloride cotransporter by a PKC-independent pathway PNAS, December 11, 2007; 104(50): 20120 - 20125. [Abstract] [Full Text] [PDF] S. Yasuda, R. L. Stevens, T. Terada, M. Takeda, T. Hashimoto, J. Fukae, T. Horita, H. Kataoka, T. Atsumi, and T. Koike Defective Expression of Ras Guanyl Nucleotide-Releasing Protein 1 in a Subset of Patients with Systemic Lupus Erythematosus J. Immunol., October 1, 2007; 179(7): 4890 - 4900. [Abstract] [Full Text] [PDF] N. Beaulieu, B. Zahedi, R. E. Goulding, G. Tazmini, K. V. Anthony, S. L. Omeis, D. R. de Jong, and R. J. Kay Regulation of RasGRP1 by B Cell Antigen Receptor Requires Cooperativity between Three Domains Controlling Translocation to the Plasma Membrane Mol. Biol. Cell, August 1, 2007; 18(8): 3156 - 3168. [Abstract] [Full Text] [PDF] J. P. Roose, M. Mollenauer, M. Ho, T. Kurosaki, and A. Weiss Unusual Interplay of Two Types of Ras Activators, RasGRP and SOS, Establishes Sensitive and Robust Ras Activation in Lymphocytes Mol. Cell. Biol., April 1, 2007; 27(7): 2732 - 2745. [Abstract] [Full Text] [PDF] S. Han, S. M. Knoepp, M. A. Hallman, and K. E. Meier RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells Mol. Pharmacol., January 1, 2007; 71(1): 314 - 322. [Abstract] [Full Text] [PDF] H. Beaudry, L. Gendron, M.-O. Guimond, M. D. Payet, and N. Gallo-Payet Involvement of Protein Kinase C{alpha} (PKC{alpha}) in the Early Action of Angiotensin II Type 2 (AT2) Effects on Neurite Outgrowth in NG108-15 Cells: AT2-Receptor Inhibits PKC{alpha} and p21ras Activity Endocrinology, September 1, 2006; 147(9): 4263 - 4272. [Abstract] [Full Text] [PDF] J. J. Coughlin, S. L. Stang, N. A. Dower, and J. C. Stone RasGRP1 and RasGRP3 Regulate B Cell Proliferation by Facilitating B Cell Receptor-Ras Signaling J. Immunol., December 1, 2005; 175(11): 7179 - 7184. [Abstract] [Full Text] [PDF]

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