This proposal outlines a training program that will enable the transition to an independent career in cancer research. The candidate has a Ph.D. in Biomedical Sciences and is trained in genetic and biochemical techniques used to study cell motility and cell signaling. She is currently mentored by Dr. John Blenis, Professor of Cell Biology at Harvard Medical School. Dr. Blenis is one of the world's leaders in mechanistic dissection of the Ras/ERK and PI3K/mTORC1 oncogenic signaling pathways. The training program includes new mentoring from Dr. Gaudenz Danuser, Professor of Cell Biology at Harvard Medical School. Dr. Danuser is an innovator in developing new computational methods to address previously un-attainable questions in chemical and mechanical signaling. The candidate is researching the transcription-independent mechanisms by which ERK and RSK regulate cell motility in untransformed model cells and transformed cancer cells. In the short term, the proposed research program will provide training in advanced quantitative imaging of actomyosin dynamics, a new technique for the candidate, and will provide time for her to publish additional manuscripts and transition her studies cancer cell migration and invasion. She has identified several components of the actomyosin machinery, such as MYPT1, as novel ERK/RSK substrates and will further investigate their role in driving cancer cell migration and invasion. Thus, this training program will prepare the candidate to become an independent scientist, with a long-term research program that integrates biochemical studies with microscopy-based dissection of cytoskeletal dynamics to understand the signaling mechanisms that drive cancer cell motility. This basic research will uncover fundamental mechanisms of cancer cell migration relevant to multiple cancer types and will inform upon therapeutic strategies targeting cancers with activated ERK/RSK signaling.
Cancer mortality is primarily due to the effects of invasive cancer spreading to other organs. We have identified, and propose to further investigate, a role for the oncogenic ERK/RSK signaling pathway in driving cancer cell migration and invasion. My goals are to understand the molecular basis of how mutations that activate the ERK/RSK pathway regulate the actomyosin cytoskeleton to induce cancer cell motility. Our findings will inform upon treatments strategies aimed at preventing cancer's metastatic spread.
|Mendoza, Michelle C; Vilela, Marco; Juarez, Jesus E et al. (2015) ERK reinforces actin polymerization to power persistent edge protrusion during motility. Sci Signal 8:ra47|
|Mendoza, Michelle C (2013) Phosphoregulation of the WAVE regulatory complex and signal integration. Semin Cell Dev Biol 24:272-9|
|Er, Ekrem Emrah; Mendoza, Michelle C; Mackey, Ashley M et al. (2013) AKT facilitates EGFR trafficking and degradation by phosphorylating and activating PIKfyve. Sci Signal 6:ra45|
|Zhang, Wenjuan; Mendoza, Michelle C; Pei, Xiaolei et al. (2012) Down-regulation of CMTM8 induces epithelial-to-mesenchymal transition-like changes via c-MET/extracellular signal-regulated kinase (ERK) signaling. J Biol Chem 287:11850-8|