A migrating cell changes its shape during the cyclic events of attachment and detachment from the substratum and repositions the cell organelles correspondingly. These complex events are orchestrated by the dynamic cytoskeletal network comprising actin filaments, intermediate filaments, and microtubules. Cytoskeletal crosstalk — the direct and indirect communication between the different components — is crucial for this coordination. Direct communication involves various linker proteins that form cross-bridges between the components. For example, the linker protein spectraplakin bridges microtubules with actin filaments, and KASH proteins link the nucleus to the cytoskeleton. Indirect communication is mediated via signaling cascades, such as those involving the Rho proteins.

Rho, the Master Regulators

The small GTPases of the Rho family proteins, such as RhoA, Cdc42, and Rac1, are the master regulators in establishing cell polarity by acting on all three cytoskeletal components. For example, Cdc42 not only directs actin reorganization at the leading edge but also reorganizes intermediate filaments by regulating their transport on the microtubules. The microtubules also direct the transport of various proteins and vesicles, which, in turn, regulate actin dynamics at the leading edge. Such positive feedback helps maintain the synchronized polarity of the different cytoskeletal components.