The Ras GTPase Activating Protein p120 RasGAP as a Regulator of Cardiovascular System Development, Lymphatic System Maintenance, and a T Cell Lineage Tumor Suppressor.

[摘要] Ras signaling activates multiple pathways that drive cell growth, proliferation, survival, and differentiation. Ras is activated downstream of multiple receptors by the recruitment and interaction with Ras guanine nucleotide exchange factors (RasGEFs). Efficient regulation of this signaling is essential for the avoidance of developmental defects and cancer, and cessation of Ras signaling is dependent on the recruitment of Ras GTPase activating proteins (RasGAPs) for juxtaposition with Ras. RasGAPs physically interact with Ras to allow for Ras hydrolization of bound GTP.There are multiple RasGAPs, which have varied tissue expression patterns. The RasGAP p120 RasGAP (RASA1) has been shown to be important in the mouse embryonic cardiovasculature and adult lymphatic system. However, RASA1 has other roles than regulation of Ras, including interactions with p190 RhoGAP for directed cell migration. To address this, we generated a mouse carrying a point mutation in its GAP domain that ablates its GAP activity while retaining all other functions. With the use of these mice we show that it is the loss of RASA1’s ability to regulate Ras that results in failed cardiovascular development in embryos and the instability and outgrowth of lymphatic vessels in adult mice.Although RASA1 plays an important role in many tissues, it has a minor role in the regulation of Ras during T cell development.Another RasGAP, Neurofibromin 1 (NF1) also appears to have a largely dispensable function in the T cell compartment.Since loss of both RASA1 and NF1 in developing embryos results in earlier embryonic lethality than loss of either RasGAP alone, we hypothesized that these RasGAPs may have overlapping functions in T cells.Indeed, concurrent deletion of RASA1 and NF1 in the T cell compartment resulted in in a randomly occurring T cell acute lymphoblastic leukemia (T-ALL) in mice associated with acquisition of somatic activating mutations in the Notch1 receptor previously implicated in T-ALL pathogenesis.

[发布机构] University of Michigan

[效力级别] Microbiology and Immunology

[关键词] RasGAP;Microbiology and Immunology;Molecular;Cellular and Developmental Biology;Health Sciences;Science;Immunology