This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. T cell acute lymphoblastic leukemia/lymphoma (TALL/L) involves abnormal proliferation of lymphocytes, or white blood cells. TALL/L patients often show elevated levels of the active form of the oncoprotein, RasGTP, in blood and bone marrow cells. In contrast to other cancers, few of these TALL/L patients have the typical mutations in Ras protein that would explain this accumulation. This finding suggests that many TALL/L patients have abnormal expression or activity of signaling proteins upstream of RasGTP. Lymphocytes express two Ras guanine nucleotide exchange factors (RasGEFs), SOS and RasGRP1, which work together to activate Ras when cell surface receptors are stimulated. Previous work demostrated that RasGRP1 is the dominant RasGEF in lymphocytes after antigen receptor stimulation. Mice overexpressing wild type RasGRP1 develop thymomas and skin carcinomas. Thus non-cancerous cells must have a mechanism to limit RasGRP1 function. Surprisingly, the negative regulatory factors that turn off this strong, RasGRP1-driven growth signal and prevent uncontrolled proliferation are unknown. Control of signals received via receptor binding can occur through posttranslational modification of signaling components. Decreases in RasGRP1 protein level after T cell receptor (TCR) stimulation precedes RasGRP1 transcript degradation. This study will identify the posttranslational modification events controlling RasGRP1 protein levels and activity within lymphocytes. The proposed experiments will use Mass Spectrometry to examine posttranslational modification events that occur on RasGRP1 protein following TCR stimulation. Modified sites identifed will give us insight into the control of RasGRP1 activity in normal lymphocytes and provide mechanistic clues for TALL/L patient samples with mutated forms of RasGRP1.
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