Dynamic interplay of two molecular switches enabled by the MEK1/2–ERK1/2 and IL-6–STAT3 signaling axes controls epithelial cell migration in response to growth factors

Cell migration is an essential physiological process, and aberrant migration of epithelial cells underlies many pathological conditions. However, the molecular mechanisms governing cell migration are not fully understood. We report here that growth factor–induced epithelial cell migration is critically dependent on the crosstalk of two molecular switches, namely phosphorylation switch (P-switch) and transcriptional switch (T-switch). P-switch refers to dynamic interactions of deleted in liver cancer 1 (DLC1) and PI3K with tensin-3 (TNS3), phosphatase and tensin homolog (PTEN), C-terminal tension, and vav guanine nucleotide exchange factor 2 (VAV2) that are dictated by mitogen-activated protein kinase kinase 1/2–extracellular signal–regulated protein kinase 1/2–dependent phosphorylation of TNS3, PTEN, and VAV2. Phosphorylation of TNS3 and PTEN on specific Thr residues led to the switch of DLC1–TNS3 and PI3K–PTEN complexes to DLC1–PTEN and PI3K–TNS3 complexes, whereas Ser phosphorylation of VAV2 promotes the transition of the PI3K–TNS3/PTEN complexes to PI3K–VAV2 complex. T-switch denotes an increase in C-terminal tension transcription/expression regulated by both extracellular signal–regulated protein kinase 1/2 and signal transducer and activator of transcription 3 (STAT3) via interleukin-6–Janus kinase–STAT3 signaling pathway. We have found that, the P-switch is indispensable for both the initiation and continuation of cell migration induced by growth factors, whereas the T-switch is only required to sustain cell migration. The interplay of the two switches facilitated by the interleukin-6–Janus kinase–STAT3 pathway governs a sequence of dynamic protein–protein interactions for sustained cell migration. That a similar mechanism is employed by both normal and tumorigenic epithelial cells to drive their respective migration suggests that the P-switch and T-switch are general regulators of epithelial cell migration and potential therapeutic targets.