FIG. 9.

Model for integration of TGF-β and RTK signaling through RIN1. RIN1 facilitates TβR internalization through RAB5-mediated, clathrin-dependent endocytosis, which enhances TβR signaling through the adaptor SARA, SMAD2/3 phosphorylation and association with SMAD4, and induction of SNAI1. SNAI1 represses RIN1, leading to reduced TβR signaling and creating a self-regulated circuit (enclosed by dotted lines). Endocytosis of RTKs (e.g., EGFR and MET), facilitated by RIN1 through RAB5, curtails downstream signaling through these receptors. TβR and RTK signals cooperate to strongly silence RIN1 expression through SNAI1 transcription (TβR-SMAD) and SNAI1 protein stabilization (GSK3β). Depletion of RIN1 enhances RTK signal intensity and promotes growth factor-directed migration of tumor cells. PI3K, phosphatidylinositol 3-kinase.