Assistant Professor of Oncological Sciences
B.S. Pennsylvania State University
Ph.D. University of California, San Diego
Michelle Mendoza's Lab Page
Michelle Mendoza's PubMed Literature Search
Molecular Biology Program
Cell motility, cancer, signaling, MAPK
Cell migration and invasion are essential to embryogenesis, immune system function, wound healing, and cancer dissemination. Cell movement involves cycles of leading edge protrusion and adhesion to the extracellular substrate, followed by de-adhesion and contraction of the cell body and rear. Decades of study have found this movement is highly orchestrated, involving mechanical changes in the actomyosin cytoskeleton and adhesions. Yet we still do not understand the molecular controls that balance and order these structural changes in space and time. Recent advances in proteomics and quantitative imaging now allow scientists and mathematicians to tease out unique and redundant signaling inputs into the motility process. We are using these techniques to understand how extracellular signals impinge on cytoskeletal dynamics and how oncogenic pathway hyperactivation impacts cancer invasion.
The Ras/ERK-MAPK signaling pathway is one of the most commonly activated pathways in solid tumors. We have found that ERK acts on the actin assembly machinery to directly promote rapid and sustained edge protrusion during cell movement. ERK phosphorylates the WAVE Regulatory Complex, which promotes WAVE’s interaction with, recruitment, and activation of the Arp2/3 actin nucleator at the cell edge. This increases actin assembly rates, which generates the pushing force needed to move the membrane forward. We are now characterizing additional ERK pathway inputs into the cytoskeleton and adhesion machinery. We make use of a mix of biochemical approaches involving phosphosite mutants, quantitative live-cell imaging of the cytoskeleton, and optogenetics to discover the function and order of each biochemical input. We are also working to generate in situ cancer models using explant cultures to study the role of these oncogenic signals in cancer invasion and dissemination.
- Michelle C. Mendoza*, Marco Vilela*, Jesus E. Juarez, John Blenis, and Gaudenz Danuser. ERK Reinforces Actin Polymerization to Power Persistent Edge Protrusion during Motility. Science Signaling 8(377):ra47 (2015).
- E. Emrah Er, Michelle C. Mendoza, Ashley M. Mackey, Lucia E. Rameh, and John Blenis. AKT Facilitates EGFR Trafficking and Degradation by Phosphorylating and Activating PIKfyve. Science Signaling 6(279):ra34 (2013). PMC4041878.
- Michelle C. Mendoza. Phosphoregulation of the WAVE Regulatory Complex and Signal Integration. Seminars in Cell and Developmental Biology 24(4):272-9 (2013). PMC3637877.
- Wenjuan Zhang, Michelle C. Mendoza, Xiaolei Pei, Didem Ilter, Sarah J. Mahoney, Yingmei Zhang, Dalong Ma, John Blenis, and Ying Wang. Down-regulation of CMTM8 Induces Epithelial-to-Mesenchymal-like Changes via c-MET/Extracellular Signal-Regulated Kinase (ERK) signaling. Journal of Biological Chemistry 287:11850-8 (2012). PMC3320933.
- Michelle C. Mendoza, Sebastien Besson, and Gaudenz Danuser. Quantitative Fluorescent Speckle Microscopy (QFSM) to Measure Actin Dynamics. Current Protocols in Cytometry 62:2.18.1-2.18.25 (2012). PMC3688286.
- Michelle C. Mendoza, E. Emrah Er*, Wenjuan Zhang*, Bryan A. Baliff, Hunter L. Elliott, Gaudenz Danuser, and John Blenis. ERK-MAPK Drives Lamellipodia Protrusion by Activating the WAVE2 Regulatory Complex. Molecular Cell 41:661-71 (2011). PMC3078620.
- Michelle C. Mendoza, E. Emrah Er, and John Blenis. The Ras-ERK and PI3K-mTOR Pathways: Cross-talk and Compensation. Trends in Biomedical Sciences 36:320-8 (2011). PMC3112285.