A unifying structural basis of microtubule-mediated signal transduction
Michel O. Steinmetz
Paul Scherrer Institute, Villigen PSI, Switzerland
Microtubules are traditionally viewed as downstream elements in receptor-mediated signaling, with well-characterized roles in regulating their dynamics and organization. However, they are also known to act upstream as signal transducers in key pathways such as Rho, Hedgehog, Wnt, Jnk, and G-protein signaling. These microtubule-mediated signaling activities influence essential cellular processes including differentiation, locomotion, polarization, proliferation, mechanotransduction, senescence, apoptosis, tumor suppression, development, and immune response. While several classes of signaling molecules have been identified as relays from microtubules to downstream targets, the mechanism by which microtubules regulate these molecules remained unclear.
We identify the structural basis by which microtubules regulate the guanine nucleotide exchange factor H1 (GEFH1), a key RhoA pathway activator. Specific microtubule lattice features bind GEFH1’s C1 domain, sequestering and inactivating it. Mutations in C1 residues disrupt this interaction, releasing GEFH1 and activating RhoA-dependent immune responses. Extending this mechanism, we identify microtubule-binding C1 domains in other signaling proteins, including other GEFs, kinases, a GTPase-activating protein, a tumor suppressor, and an oncoprotein. We validate this regulatory mechanism in the tumor suppressor RASSF1A, showing that microtubule-mediated control via C1 domains is conserved.
Our findings define a unifying structural framework for microtubule-mediated signaling, resolving how diverse signaling proteins are modulated by microtubules. This reconceptualizes microtubules as spatiotemporal signal transducers—both receivers and mediators in signaling pathways. This work opens avenues for systematic investigation into microtubule-based signal integration and processing, including whether the primary role of microtubule dynamics in stable interface-tissue cells is to maintain intracellular signaling homeostasis.
