Our laboratory is interested in genetic lesions that lead to abnormal signal transduction events and development of diseases like autoimmunity and cancer.
Our goal is to understand the mechanism of activation of the small GTPase Ras, comparing normal physiology with pathology. Active Ras communicates to many downstream targets and affects many cell biological responses. The potency of active Ras as a signaling molecule is illustrated by the fact that activating mutations in the Ras genes are among the most common genetic lesions leading to many types of cancer.
We have used primary lymphocytes and cell lines to unravel the molecular and biochemical events that lead to Ras activation when antigen receptors are triggered on the surface of lymphocytes. Lymphocytes express two types of Ras activators, RasGRP and SOS, which operate through distinct mechanisms and can elicit distinct patterns of Ras activation. We are interested in understanding what these distinct patterns mean in terms of normal lymphocyte development, but also with regards to autoimmune diseases and cancer.
We collaborate with many different groups inside and outside of UCSF and benefit from these collaborations by tapping into computational models, biophysical approaches, structural insights, and patient samples. We combined these collaborative efforts with our own expertise in the biochemistry of Ras signal transduction, cell line approaches, and various mouse models to understand how alterations in Ras signals form the origin of various pathological disease processes.
Abel SM, Roose JP, Groves JT, Weiss A, Chakraborty AK. The Membrane Environment Can Promote or Suppress Bistability in Cell Signaling Networks. J Phys Chem B. 2012 Mar 13.
Evan Markegard, Evan Trager, Chih-wen Ou Yang, Weiguo Zhang, Arthur Weiss, and Jeroen P. Roose. Basal LAT-diacylglycerol-RasGRP1 Signals in T cells Maintain TCR-alpha Gene Expression. PLoS ONE, 2011;6(9):e25540. Epub 2011 Sep 26.
Andre Limnander, Philippe Depeille, Jen Liou, Micheal Leitges, Jeroen P. Roose, and Arthur Weiss. Stim1 and PKC Set a Threshold for Activation of Pro-Apoptotic Erk Signaling During B cell Development. Nature Immunology, May 2011.
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. 2009 Sep 17;461(7262):411-4.
Chakraborty AK, Das J, Zikherman J, Yang M, Govern CC, Ho M, Weiss A, and Roose J. Molecular origin and functional consequences of digital signaling and hysteresis during Ras activation in lymphocytes. Science Signaling. 2009 2, 66:pt2.
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