Signaling in cytoskeletal dynamics
Signaling in cytoskeletal dynamics
RAS/ERK Signaling
The oncogenic RAS®RAF®MEK®ERK signaling pathway is activated during development, wound healing, and cancer. Growth factors and oncogenic mutations activate the small GTPase Ras and the downstream kinase RAF, which signal to the ERK mitogen-activated protein kinase (MAP kinase). The pathway is also activated by stretch and cell surface receptors for the extracellular matrix, call integrins. By studying previously unappreciated substrates of ERK and its downstream kinase p90 Ribosomal S6 Kinase (RSK), we are discovering the mechanistic details behind how this pathway generates the forces that drive migration. This project is funded by R01GM141372.
- Mendoza et al., TIBS 2011
- Samson et al., Frontiers Mol Biosci 2022
Cell Migration and Invasion
In our bodies, epithelial cells invade into tissue by migrating along tracks of extracellular matrix or paths created by support cells like fibroblasts. The cells move in a mesenchymal mode also observed in vitro, in which a leading edge cycles through protrusion and retraction. In protrusion, assembly of the actin polymer against the membrane generates pushing force, the membrane counters with tension. Adhesions transmit traction force. A few microns behind the edge, myosin motors pull on the actin, generating tension that balances the pushing force and promotes adhesion maturation. In the cell body, myosin II contracts bundled actin fibers (stress fibers) that anchor to adhesions, which contracts the back of the cell forward
ERK controls pushing force at the cell edge
ERK promotes edge protrusion, the first step of cell motility by directly phosphorylating the WAVE Regulatory Complex (WRC). WRC phosphorylation increases recruitment of the actin nucleator ARP2/3 to the cell edge, where it induces actin assembly that pushes the membrane outwards. In addition, we discovered that ERK promotes both the assembly and disassembly of nascent adhesions at the cell edge, building a population of small, rapidly turning over adhesions. Computational modeling showed that this nascent adhesion traction force promotes protrusion velocity without limiting persistence. Thus, ERK directly controls both actin assembly and adhesion dynamics at the cell edge to generate stable pushing force for cell migration.
- Mendoza, et al. Mol Cell (2011)
- Mendoza, et al. Sci Signaling (2015)
- Carney et al. MBoC (2023)
- Shepherd, et al. BioRxiv (2025)
ERK controls Rho and myosin
ERK has long been known to induce the Rho GTPase, myosin II, and actin stress fibers needed for cell migration and other cellular processes. Our biochemical and biosensor studies are deducing the molecular mechanisms behind these regulations. We discovered that ERK acts through lymphocyte-oriented kinase (LOK) to promote Rho activity for the assembly of stress fibers in the cell body. ERK phosphorylation of LOK inactivates LOK’s activation of Ezrin, which blocks Ezrin’s recruitment of the Rho GTPase activating protein GAP18. With less GTPase activity, Rho stays in its active, GTP-bound form and builds stress fibers in the cell body. We found that ERK induces myosin by signaling through p90 ribosomal S6 kinase (RSK). RSK inhibits the myosin phosphatase by phosphorylating the myosin regulatory subunit MYPT1, which promotes phosphatase inactivation by the kinase ROCK. By inactivating the phosphatase, ERK releases myosin activity.
- Samson, et al. JBC (2019)
- Khan, et al. BioRxiv (2025)
Current projects: control and integration of the fluctuating molecular forces of cell migration
Our current work focuses understanding the role of spatially-organized ERK activity through optogenetics and determining how ERK/RSK substrates control cell migration in response to biophysical cues, such as cell stretch and substrate stiffness.
Affiliations
- Department of Oncological Sciences
- Department of Biomedical Engineering
- Cancer Biology and Microenvironment Program
- Lung Center of Excellence
- Computational Oncology Research Initiative
- Molecular Biology Graduate Program
Collaborations
Mechanobiology: The Mendoza lab has a funded collaboration with the Weiss lab in the Biomedical Engineering department. This collaboration applies computational modeling and experimental stretching of lung tissue to understand the biomechanical signals involved in lung tumor growth.
Pollution and lung cancer: The Mendoza has lab a funded collaboration with Drs. Judy Ou and Chen Chen in Population Health Sciences to understand and target the cancer-promoting signals in particulate matter pollution.
Pathology: Support is also provided by Dr. Lyska Emerson in the Department of Pathology.