Our laboratory is studying the role of physical forces for activation of the Notch receptor. The Notch receptor is curious in its general requirement for ligand endocytosis for generating Notch signals. That is to say, ligand presented on the signal-sending neighboring cell, must be endocytosed by that cell to activate Notch. This so called pulling force model is a special case of mechanotransduction for which mechanical forces appear required for signaling, but the cells are not probing their mechanical microenvironment. The figure below illustrates this pulling force model as put forth by our collaborator Professor Gerry Weinmaster (retired) formally of UCLA.
Together we demonstrated that Notch signaling was dependent up Mib-mediated ligand ubiquitylation, the endocytic machinery components clatherin, dynamic, and epsins, as well as actin polymerization inside of the ligand cell. This finding suggests that the endocytic machinery in a ligand cell applies physical force through a Notch-ligand interaction to unfold notch for signaling. Curiously, we found that while the rupture force of the Notch-ligand interaction was independent on these factors (Shergill et al.), the ability of the ligand to generate force was dependent on these factors (Meloty-Kapella et al.).
We are currently studying the mechanical work required for Notch activation.