Investigating the biochemical and oncogenic properties of the Ras GTPase RIT1

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Project Summary/Abstract RIT1 is a member of the Ras family of GTPases that direct broad cellular physiological responses through tightly controlled signaling networks. RIT1 has been recently described as an oncogenic driver of lung adenocarcinoma and myeloid malignancies. Despite the emerging role of RIT1 mutations in cancer, RIT1 remains a poorly studied member of the Ras GTPase family. To identify and characterize properties of RIT1 that may contribute to the pathogenesis of RIT1 disease, we performed a mass spectrometry-based screen that identified a direct link with components of the spindle assembly checkpoint (SAC), a critical pathway necessary for proper chromosome segregation during mitosis. Characterization of this novel interaction has revealed that mutant RIT1 promotes aneuploidy by suppressing the SAC. Despite our preliminary evaluation, further analyses are required to understand the physiological function of this interaction and the contribution of SAC dysregulation to RIT1 oncogenicity. The objective of this proposal is to evaluate the biochemical and oncogenic properties of RIT1 associated with SAC suppression. The specific aims are to 1) interrogate the physiological function and regulation of the RIT1-SAC interaction and 2) examine the molecular determinants of RIT1-mediated oncogenicity. Aim 1 will be achieved using biochemical, structural, and cell biological approaches to assess the regulation of the RIT1-SAC interaction, its structural characteristics, and its functional consequences using primary gain-of-function and loss-of-function cell models. Aim 2 will focus on a set of ongoing RIT1 mouse model studies to a) assess the contribution of the RIT1-SAC interaction to RIT1 oncogenicity and b) identify secondary genetic lesions that contribute to the development of RIT1-driven tumors. The proposed research will help elucidate the mechanism of RIT1-mediated tumorigenesis in order to identify potential vulnerabilities that can be explored for the development of therapeutic strategies. The research strategy described in this proposal will be conducted in the lab of Dr. Frank McCormick at the UCSF Helen Diller Family Comprehensive Cancer Center. The fellowship training plan incorporates professional and career development activities aimed at 1) building upon my technical skillset in biochemistry and cancer biology, 2) improving my communication skills, 3) developing effective teaching and mentoring skills, and 4) preparing me for a postdoctoral training position. Completion of these goals would provide the experience and expertise necessary to embark on an independent research career to continue investigating the molecular mechanisms underlying the dysregulation of signal transduction pathways that contribute to cancer development and disease progression.