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Originally published as MBC in Press, 10.1091/mbc.E06-10-0932 on June 13, 2007

Vol. 18, Issue 8, 3156-3168, August 2007

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Regulation of RasGRP1 by B Cell Antigen Receptor Requires Cooperativity between Three Domains Controlling Translocation to the Plasma Membrane

Nadine Beaulieu, Bari Zahedi, Rebecca E. Goulding, Ghazaleh Tazmini, Kira V. Anthony, Stephanie L. Omeis, Danielle R. de Jong, and Robert J. Kay

Terry Fox Laboratory, British Columbia Cancer Research Centre, Vancouver, BC, Canada V5Z 1L3

Submitted October 19, 2006; Revised May 24, 2007; Accepted May 31, 2007
Monitoring Editor: Robert Parton

RasGRP1 is a Ras-activating exchange factor that is positively regulated by translocation to membranes. RasGRP1 contains a diacylglycerol-binding C1 domain, and it has been assumed that this domain is entirely responsible for RasGRP1 translocation. We found that the C1 domain can contribute to plasma membrane-targeted translocation of RasGRP1 induced by ligation of the B cell antigen receptor (BCR). However, this reflects cooperativity of the C1 domain with the previously unrecognized Plasma membrane Targeter (PT) domain, which is sufficient and essential for plasma membrane targeting of RasGRP1. The adjacent suppressor of PT (SuPT) domain attenuates the plasma membrane-targeting activity of the PT domain, thus preventing constitutive plasma membrane localization of RasGRP1. By binding to diacylglycerol generated by BCR-coupled phospholipase C{gamma}2, the C1 domain counteracts the SuPT domain and enables efficient RasGRP1 translocation to the plasma membrane. In fibroblasts, the PT domain is inactive as a plasma membrane targeter, and the C1 domain specifies constitutive targeting of RasGRP1 to internal membranes where it can be activated and trigger oncogenic transformation. Selective use of the C1, PT, and SuPT domains may contribute to the differential targeting of RasGRP1 to the plasma membrane versus internal membranes, which has been observed in lymphocytes and other cell types.

This was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-10-0932) on June 13, 2007.

Address correspondence to: Robert Kay (rkay{at}bccrc.ca).

Abbreviations used: BCR, B cell antigen receptor; DAG, diacylglycerol; GFP, green fluorescent protein; PLC, phospholipase C; TCR, T cell antigen receptor.






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