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Open Access Publications from the University of California

Scholarly Works (2 results)

  • Thesis
  • Peer Reviewed
UC San Francisco Electronic Theses and Dissertations (2011)

Lymphocytes express two Ras guanine exchange factors (RasGEFs), Sos and RasGRP1, which can act in concert to activate the Ras-MEK-ERK pathway downstream of antigen receptor signaling. RasGRP1 is capable of priming Sos and is required for optimal Sos activation. Sos is incapable of compensating for loss of RasGRP1 in lymphocytes as RasGRP1-deficient mice fail to develop single positive thymocytes. Conversely, overexpression of RasGRP1 in the thymus leads to the development of thymomas. Since RasGRP1 exists in this critical position between immunodeficiency and oncogenesis, it is important to understand the mechanisms underlying the regulation of RasGRP1 protein levels and activity.

My studies suggest that posttranslational modifications of RasGRP1 exist to limit RasGRP1 activity after antigen receptor stimulation. RasGRP1 appears to be monoubiquitinated and is phosphorylated in the basal state as well as upon TCR stimulation. Additionally, a hypomorphic allele of RasGRP1 (RasGRP1Anaef) leads to relatively normal thymocyte development in the context of a wildtype TCR repertoire, but a modest impairment in positive selection is revealed when a transgenic TCR is used. Surprisingly, mice expressing this allele have appear to have phenotypically activated T cells, produce anti-nuclear antibodies and have hypercellular spleens by the age of 12 weeks. It appears that RasGRP1 may play a role in negatively regulating TCR signaling that was previously unrecognized. Thus, RasGRP1 must be properly regulated to prevent autoimmunity as well. Further work examining RasGRP1 protein function and regulation is required to understand the possibility and implications pharmacological targeting of this critical RasGEF in the disease state.

    Cover page: Regulation of RasGRP1 protein in thymocyte development and peripheral T cells
    • Article
    • Peer Reviewed
    UC San Francisco Previously Published Works (2013)
    Enhanced signaling by the small guanosine triphosphatase Ras is common in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), but the underlying mechanisms are unclear. We identified the guanine nucleotide exchange factor RasGRP1 (Rasgrp1 in mice) as a Ras activator that contributes to leukemogenesis. We found increased RasGRP1 expression in many pediatric T-ALL patients, which is not observed in rare early T cell precursor T-ALL patients with KRAS and NRAS mutations, such as K-Ras(G12D). Leukemia screens in wild-type mice, but not in mice expressing the mutant K-Ras(G12D) that encodes a constitutively active Ras, yielded frequent retroviral insertions that led to increased Rasgrp1 expression. Rasgrp1 and oncogenic K-Ras(G12D) promoted T-ALL through distinct mechanisms. In K-Ras(G12D) T-ALLs, enhanced Ras activation had to be uncoupled from cell cycle arrest to promote cell proliferation. In mouse T-ALL cells with increased Rasgrp1 expression, we found that Rasgrp1 contributed to a previously uncharacterized cytokine receptor-activated Ras pathway that stimulated the proliferation of T-ALL cells in vivo, which was accompanied by dynamic patterns of activation of effector kinases downstream of Ras in individual T-ALLs. Reduction of Rasgrp1 abundance reduced cytokine-stimulated Ras signaling and decreased the proliferation of T-ALL in vivo. The position of RasGRP1 downstream of cytokine receptors as well as the different clinical outcomes that we observed as a function of RasGRP1 abundance make RasGRP1 an attractive future stratification marker for T-ALL.
      Cover page: Dysregulated RasGRP1 Responds to Cytokine Receptor Input in T Cell Leukemogenesis
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