UCSF

The ability of cells to generate a coordinated response to the biochemical and physical cues in the microenvironment is fundamental to development and disease. Signaling pathways integrate these cues through physical and functional interactions among ligands, receptors, and effectors. Cell surface receptors, in particular, undergo spatially regulated organization and multimerization to calibrate the quality, intensity, and duration of the signal and response. However, the mechanisms by which receptors enable the cell to achieve a concerted response to diverse biochemical and physical cues remain unclear. Elucidating these mechanisms is essential for understanding how the cellular microenvironment regulates growth factor signaling. To investigate these spatial and molecular mechanisms, we optimized novel high-resolution and single particle tracking imaging techniques and utilized established biochemical assays to examine TGFβ signaling. TGFβ receptors type I and II are discretely localized to segregated spatial domains at the cell surface. Interestingly, integrin-rich focal adhesions organize TβRII around TβRI, altering receptor mobility and limiting the integration of TβRII while sequestering TβRI at these sites. Disruption of cellular tension leads to a collapse of this highly ordered and unique spatial organization of TGFβ receptors at sites of adhesions. Furthermore, a change in cellular tension through ROCK inhibition or culturing cells on compliant substrates drives the formation of heteromeric TβRI/TβRII complexes and the phosphorylation of downstream TGFβ effector Smad3. This work details a novel mechanically-regulated mechanism whereby focal adhesions and cell tension control the spatial organization, multimerization, and signaling of growth factor receptors in the TGFβ pathway, providing new insight into the cellular mechanisms that integrate biochemical and physical cues.