Immunology Graduate Program | University of California, San Francisco

Jeroen Roose, PhD

Ras Signal Transduction in Lymphocytes and Cancer

Assistant Professor, Department of Anatomy
University of California, San Francisco
513 Parnassus Ave., Rm. HSW-1326, Box 0452
San Francisco, CA 94143-0452

(415) 476-3977 office tel.
(415) 476-4322 lab tel.
(415) 476-4845 fax
jeroen.roose@ucsf.edu

Anatomy web page
BMS web page
Cancer Center web page

AA: Sharon Spencer
(415) 502-5659 tel.

Description of Research

Lymphocytes are dynamic cells in terms of cellular activity, undergoing distinct stages of proliferation not only during their development but also once they are matured (e.g. in response to pathogens). The dynamic nature of these cells can also be appreciated at the level gene expression programs and unique control mechanisms are required to maintain these programs. Our lab investigates how the robust but controlled changes in both cellular activity and gene expression profiles come about. In particular, we are focusing on the role of the Ras-MAP kinase pathway.

We previously mapped a very active pathway that depends generation of diacylglycerol (DAG) in T and B cells. DAG recruits PKC kinases and the Ras activator RasGRP to the membrane (where Ras resides). Lymphocytes express a second type of Ras activator, SOS, which is also recruited to the membrane when antigen or growth factor receptors are stimulated. We determined that an unusual connection between RasGRP and SOS is responsible for robust, but controlled, Ras activation in lymphocytes. RasGRP functions as a trigger, and SOS acts as an amplifier that operates through a positive feedback loop. Either Ras activator alone cannot achieve the sensitivity and robustness in Ras activation (characteristic for lymphocytes) without loss of control. In fact, we have identified the RasGRP1 locus as a frequent integration site in random retroviral screen for aberrantly expressed genes that can drive T cell lymphomagenesis in vivo . In the resting state, RasGRP-SOS crosstalk is important to maintain normal basal levels of Ras signaling in quiescent lymphocytes, a process that we have shown regulates gene expression profiles. These studies implicate that unbalanced RasGRP and SOS function will lead to aberrant levels of active Ras, occurring in the basal and receptor-triggered state.

We are building on these findings using mathematical simulations and cell lines as model systems to further understand the mechanism of RasGRP-SOS crosstalk and Ras signal transduction. We compare signal transduction events between normal and malignant lymphocytes and we combine these approaches with the analysis of mouse models of cancer and analysis of patient samples.

Jayajit Das, Mary Ho, Julie Zikherman, Christopher Govern, Ming Yang, Arthur Weiss, Arup K. Chakraborty, and Jeroen P. Roose. Digital Signaling and Hysteresis Characterize Ras Activation in Lymphoid Cells. Cell. 2009 136, 337-351.

Prasad, A., Zikherman, J., Das, J., Roose, J.P., Weiss, A., and Chakraborty, A.K. Origin of the sharp boundary that discriminates positive and negative selection of thymocytes. PNAS. 2009 Jan 13;106(2):528-33.

Roose, J.P., Mollenauer, M., Ho, M., Kurosaki, T., and Weiss, A.. Unusual interplay of two types of Ras activators, RasGRP and SOS, establishes sensitive and robust Ras activation in lymphocytes. Mol Cell Biol. 2007 27, 2732-2745.

Roose J, Mollenauer M, Gupta V, Stone J, and Weiss A. A Diacylglycerol-Protein Kinase C-RasGRP1 Pathway Directs Ras Activation Upon Antigen Receptor Stimulation of T cells. Mol. Cell Biol. 2005 25(11);4426-41.

Roose J, Diehn M, Tomlinson M, Lin J, Alizadeh A, Botstein D, Brown P, Weiss A. T cell Receptor-Independent Basal Signaling via Erk and Abl Kinases Suppresses RAG gene Expression. PLOS Biology. 2003 1(2):271-287.