Jeroen P. Roose PhD, Assistant Professor
jeroen.roose@ucsf.edu



Ras Signal Transduction in Lymphocytes and Cancer

My lab is interested in the regulation of Ras signal transduction and in the cellular abnormalities and disease states that arise from aberrant Ras signals. We have used lymphocytes as a model system to unravel the mechanism of Ras activation via a dominant Ras activator called RasGRP1.

Through studies of RasGRP1 we have established that: (1) constitutive Ras signals through RasGRP1 maintain stable gene expression program profiles in resting cells, preventing genetic de-differentiation. (2) Downstream of receptor- and non-receptor tyrosine kinase activation, RasGRP1 induces rapid and robust Ras activation. It does so by (1) directly acting as a Ras guanine nucleotide exchange factor (RasGEF) but also (2) indirectly by enhancing the activity of a second RasGEF, SOS. The observed sensitivity and robustness (characteristic for lymphocytes) cannot be achieved by one Ras activator alone without loss of control (e.g. development of lymphoma). At the same time RasGRP-SOS crosstalk is important to maintain normal basal levels of Ras signaling in resting cells, a process that we have shown regulates gene expression profiles. 

These findings suggest that unbalanced RasGRP and SOS function will lead to aberrant levels of active Ras, occurring either in the basal and/or receptor-triggered state, leading to dysfunctional or hyperactive lymphocytes.We are building on this hypothesis using mathematical simulations and cell lines as model systems to further understand the mechanism of RasGRP-SOS crosstalk and Ras signal transduction. In particular we compare Ras signaling events in normal lymphocytes with events occurring in lymphoma cells.

We also combine these approaches with the analysis of mouse models of lymphomagenesis and analysis of patient samples.  

Lab Members:
Postdoctoral Fellows - Phlippe Depeille, Jesse Jun
Undergrad Students - Jeroen Bakker
Graduate Students - Kristen Coakley
Staff - Ed Lemmens, Evan Trager

Complete list of Publications/PubMed 

Selected publications: 

Jennifer O. Lauchle, Doris Ki, Doan T. Le, Keiko Akagi, Michael Crone, Kimberly Krisman, Kegan Warner, Jeannette M. Bonifas, Qing Li, Kristin M. Coakley, Ernesto Diaz-Flores, Matthew Gorman, Sally Przybranowski, Mary Tran, Scott C. Kogan, Jeroen P. Roose, Neal Copeland, Nancy Jenkins, Luis Parada, Linda Wolff, Judith Sebolt-Leopold, and Kevin Shannon. Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras. Nature, in press, doi:10.1038/nature08279

Ashok Prasad, Julie Zikherman, Jayajit Das, Jeroen Roose, Arthur Weiss, Arup K. Chakraborty. Origin of the sharp boundary that discriminates positive and negative selection of thymocytes. PNAS. 2009 Jan 13;106(2):528-33.

Jayajit Das, Mary Ho, Julie Zikherman, Christopher Gover, 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.

Roose J, Mollenauer M, Ho M, Kurosaki T, and Weiss A. Unusual Interplay of Two Types of Ras Activators, RasGRP and SOS, Establishes Robust and Controlled Ras Activation in Lymphocytes. Mol Cell Biol. 2007 27(7):2732-45