Endocytsis of cell surface receptors plays an important role in regulating cell signaling cascades. In some cases, internalization of an activated receptor attenuates the signaling process, while in other cases, the clustering of activated receptors on early endosomal structures has been proposed to be essential for fully activating signaling cascades. Regulating the movement of receptors and other signaling proteins through the endocytic pathway, therefore, has a direct impact on cellular homeostasis.
The small GTPase Rab5 is a critical regulatory component of the endocytic pathway. Activation of Rab5 is mediated by a guanine nucleotide exchange factors that generate the active Rab5 GTP complex. We have identified a large number of proteins that contain a specific, highly conserved domain that catalyzes Rab5/Vps21p nucleotide exchange. One of these, Rin1, is itself activated by binding Ras GTP and this Ras GTP mediated activation serves as a link between signaling cascade attentuation and the endocytic pathway.
Like Rin1, other members of this protein family contain many signaling motifs in addition to their Rab5/Vps21p exchange domain. We are examining the precise functional role this family of proteins plays in regulating cell surface receptor trafficking and cell signaling in normal and disease states.