Revisiting the Role of TGF beta Receptor Internalization for Smad Signaling: It is Not Required in Optogenetic TGF beta Signaling Systems

Abstract

Endocytosis is an important process by which many signaling receptors reach their intracellular effectors. Accumulating evidence suggests that internalized receptors play critical roles in triggering cellular signaling, including transforming growth factor beta (TGF beta) signaling. Despite intensive studies on the TGF beta pathway over the last decades, the necessity of TGF beta receptor endocytosis for downstream TGF beta signaling responses is a subject of debate. In this study, mathematical modeling and synthetic biology approaches are combined to re-evaluate whether TGF beta receptor internalization is indispensable for inducing Smad signaling. It is found that optogenetic systems with plasma membrane-tethered TGF beta receptors can induce fast and sustained Smad2 activation upon light stimulations. Modeling analysis suggests that endocytosis is precluded for the membrane-anchored optogenetic TGF beta receptors. Therefore, this study provides new evidence to support that TGF beta receptor internalization is not required for Smad2 activation.