Ras Signaling and Lineage Decisions in Stem- and Progenitor- Cells
The Roose lab studies the molecular mechanisms of receptor-driven Ras signals and how these affect cell biology. We are particularly interested in the regulation of two exchange factors for Ras, RasGRP1 and SOS1, and how the interplay, contrasts, and dynamic regulation of these two RasGEFs can direct lineage decisions.
We have uncovered that RasGRP1 and SOS1 differ tremendously from a structural point of view (Iwig et al, eLIFE, 2013). Biologically, RasGRP1 and SOS1 can send very distinct types of Ras signals in lymphocytes with RasGRP1 sending analog Ras signals and SOS1 sending digital Ras signals (Das et al., Cell, 2009).
Activation of SOS1 involves the orchestrated activity of many molecular interactions within SOS1 and other molecules, which also allows for activation of pathways other than Ras (Jun et al., MCB, 20130.
Efficient autoinhibition of RasGRP1 can be overwhelmed via overexpression of RasGRP1, which is a frequent and potent pathway to T cell leukemia (Hartzell et al., Science Signaling, 2013). Pointmutation of a key regulatory domain in RasGRP1 leads to increased basal mTOR signaling and a Lupus-like autoimmune phenotype (Daley et al., eLIFE, on press). Thus, both SOS1 and RasGRP1 appear to be regulated in uniquely intricate manners and disruption of such regulation leads to various diseases.
One of the focal points of our current work is to determine how RasGRP1 and SOS1 affect lineage decisions in hematopoietic cells in the bone marrow and thymus but also in epithelial lineages in the intestine and mammary gland.