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Prepublished online as a Blood First Edition Paper on May 1, 2003; DOI 10.1182/blood-2002-11-3621. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-11-3621v1 102/4/1414    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 Teixeira, C. Articles by Stone, J. C. Search for Related Content PubMed PubMed Citation Articles by Teixeira, C. Articles by Stone, J. C. Related Collections Immunobiology Signal Transduction Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 August 2003, Vol. 102, No. 4, pp. 1414-1420 IMMUNOBIOLOGY Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3 Christine Teixeira, Stacey L. Stang, Yong Zheng, Naomi S. Beswick, and James C. Stone From the Department of Biochemistry, University of Alberta, Edmonton, Canada. Members of the RasGRP family of Ras activators have C1 domains that bind diacylglycerol (DAG) and DAG analogs such as the tumor-promoting phorbol esters. RasGRP members could be responsible for some of the DAG signaling processes that have previously been attributed to protein kinase C (PKC). We found that RasGRP3 is selectively expressed in B cells, suggesting that RasGRP3 might function downstream of the B-cell receptor (BCR). Indeed, stimulation of Ramos B cells with the DAG analog phorbol ester myristate (PMA) results in the association of RasGRP3 with the membrane fraction. However, we also made the unexpected observation that RasGRP3 is phosphorylated, coincident with Ras activation after stimulation. When inhibitors of PKC are present, Ras activation is attenuated, and this attenuation correlates with an inhibition of RasGRP3 phosphorylation. RasGRP3 is phosphorylated in vitro by PKC- and PKC-2. When ectopically coexpressed in HEK-293 cells, a dominant-activated mutant of PKC- phosphorylates RasGRP3 and enhances Ras-Erk signaling. These results provide the first indication for a functional interaction between a RasGRP family member and a dissimilar DAG binding protein. A convergent DAG signaling system could be important in fine-tuning Ras signaling during B-cell development or during the humoral immune response. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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