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Signaling in cytoskeletal dynamics

RAS/ERK Signaling

The oncogenic RAS→RAF→MEK→ERK signaling pathway drives cell migration. 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.

Diagram of RAS→RAF→MEK→ERK signaling pathway
Diagram of edge protrusion during cell migration

Cell Migration and Invasion

In our bodies, epithelial cells invade into tissue by migrating along tracks of extracellular matrix, neurons, vessels or underlying tissue. The leading 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 promoting adhesion maturation. In retraction, actin assembly collapses and tension pulls the membrane backwards.

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) on WAVE2 and ABI. WRC phosphorylation increases WRC interaction with and recruitment of the actin nucleator ARP2/3 to the cell edge. ARP2/3 induces dendritic actin polymerization. In this manner, ERK increases the actin assembly rate at the cell edge, which increases the pushing force for rapid and persistent edge protrusion.

  • Mendoza, et al. Mol Cell (2011)
  • Mendoza, et al. Sci Signaling (2015)
Diagram of WAVE regulatory complex
Diagram of myosin activity

ERK controls myosin

We have also found that ERK promotes cell migration through phosphorylation of the myosin phosphatase on the regulatory subunit MYPT1. This promotes phosphatase inactivation by Rho kinase, which results in a sweet-spot of myosin activity that promotes edge protrusion and retraction.

  • Samson, et al. JBC (2019)

Current projects: control and integration of the fluctuating molecular forces of cell migration

We are testing the hypothesis that ERK signaling directs spatially-localized and coordinated fluctuations in actin, adhesions, and membrane tension for edge motion and cell migration. Our current work focuses on mapping ERK activity during edge protrusion using new biosensors, testing the role of spatially-organized ERK activity through opto-genetics, and determining how ERK substrates control adhesions and membrane tension. This project is funded through R01GM141372.

Michelle C. Mendoza, PhD

Principal Investigator


The Mendoza lab has a funded collaborations with the Weiss lab in the Biomedical Engineering department. The collaboration applies computational modeling to understand the mechanics of tumor growth within the lung.