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Cross-talk between the microtubule and actin networks has come under intense scrutiny following the realization that it is crucial for numerous essential processes, ranging from cytokinesis to cell migration. It is becoming increasingly clear that proteins long-considered highly specific for one or the other cytoskeletal system do, in fact, make use of both filament types. How this functional duality of "shared proteins" has evolved and how their coadaptation enables cross-talk at the molecular level remain largely unknown. We previously discovered that the mammalian adaptor protein melanophilin of the actin-associated myosin motor is one such "shared protein," which also interacts with microtubules in vitro. In a hypothesis-driven in vitro and in silico approach, we turn to early and lower vertebrates and ask two fundamental questions. First, is the capability of interacting with microtubules and actin filaments unique to mammalian melanophilin or did it evolve over time? Second, what is the functional consequence of being able to interact with both filament types at the cellular level? We describe the emergence of a protein domain that confers the capability of interacting with both filament types onto melanophilin. Strikingly, our computational modeling demonstrates that the regulatory power of this domain on the microscopic scale alone is sufficient to recapitulate previously observed behavior of pigment organelles in amphibian melanophores. Collectively, our dissection provides a molecular framework for explaining the underpinnings of functional cross-talk and its potential to orchestrate the cell-wide redistribution of organelles on the cytoskeleton., Competing Interests: The authors declare no competing interest.

Highlights • Thus far the activity of four formins is modified by applied pulling force. • Force enhances the activity of formins mDia1, mDia2, and Bni1, but inhibits Cdc12. • Mechanosensitivities and mechanisms of diverse formins should be directly compared. • Physiological relevance of most formin mechanosensivities still to be determined. Fundamental cellular processes such as division, polarization, and motility require the tightly regulated spatial and temporal assembly and disassembly of the underlying actin cytoskeleton. The actin cytoskeleton has been long viewed as a central player facilitating diverse mechanotransduction pathways due to the notion that it is capable of receiving, processing, transmitting, and generating mechanical stresses. Recent work has begun to uncover the roles of mechanical stresses in modulating the activity of key regulatory actin-binding proteins and their interactions with actin filaments, thereby controlling the assembly (formin and Arp2/3 complex) and disassembly (ADF/Cofilin) of actin filament networks. In this review, we will focus on discussing the current molecular understanding of how members of the formin protein family sense and respond to forces and the potential implications for formin-mediated mechanotransduction in cells. [ABSTRACT FROM AUTHOR]