Regulated intramembrane proteolysis (RIP) represents an evolutionarily conserved process linking receptor function with transcriptional regulation. Best characterized by the Notch signaling pathway, RIP involves regulated ectodomain shedding followed by gamma-secretase-mediated release of the C-terminal, cytosolic domain. The C-terminus in turn translocates to the nucleus where it interacts with other proteins to regulate expression of specific genes. Recent studies in our laboratory have shown that megalin, a scavenger receptor in proximal tubule, is subjected to RIP in a manner very similar to that of Notch. We showed that megalin in subjected to protein kinase C-regulated, metalloprotease-mediated ectodomain shedding producing a membrane-associated C-terminal fragment (MCTF). The MCTF in turn forms the substrate for gamma-secretase. These data implicate megalin as a central element of a Notch-like signaling pathway linking protein reabsorption and gene regulation in proximal tubule. The likelihood that megalin processing plays an important role in the progression of proteinuric kidney disease is discussed.