Volume 69, Issue 10, Pages 1717-1721 (May 2006) Regulated intramembrane proteolysis of megalin: Linking urinary protein and gene regulation in proximal tubule?  D. Biemesderfer  Kidney International  Volume 69, Issue 10, Pages 1717-1721 (May 2006) DOI: 10.1038/sj.ki.5000298 Copyright © 2006 International Society of Nephrology Terms and Conditions

Figure 1 The Notch signaling pathway. Signaling (transcriptional regulation) through the Notch pathway occurs in several distinct steps. Ligand binding (step 1) initiates ectodomain shedding (step 2) by one or more metalloproteases producing a membrane-associated C-terminal fragment (NCTF for Notch C-terminal Fragment). The NCTF in turn becomes the substrate for γ-secretase (3) resulting in RIP and releasing the Notch intracellular domain into the cytosol. The NICD is translocated to the nucleus (4), where it interacts with CSL (CBF1, Su(H), Lag-1) transcription factors (5) resulting in transcriptional regulation of target genes (6). Kidney International 2006 69, 1717-1721DOI: (10.1038/sj.ki.5000298) Copyright © 2006 International Society of Nephrology Terms and Conditions

Figure 2 Immunolocalization of presenilin-1 in kidney. Perfusion-fixed rat kidney was stained with a polyclonal antipresenilin-1 antibody. Note that the staining for presenilin-1 is largely restricted to the brush border and endocytic region of proximal tubules. Kidney International 2006 69, 1717-1721DOI: (10.1038/sj.ki.5000298) Copyright © 2006 International Society of Nephrology Terms and Conditions

Figure 3 Megalin as part of a ‘Notch-like’ signaling pathway in the proximal tubule. This scheme shows known and postulated (?) events in a proposed megalin signaling pathway. Metalloprotease (MMP) activity, activated by ligand binding (1) and regulated by protein kinase C, results in ectodomain shedding (2) of megalin. Ectodomain shedding produces an MCTF. The MCTF in turn becomes the substrate for γ-secretase activity acting in the membrane and releasing the ‘free’ C-terminal intracellular domain (megalin intracellular domain) into the cytosol (3). The megalin intracellular domain translocates (4) to the nucleus where it acts as a transcriptional regulator. Presenilin is the active component of the γ-secretase protein complex and is specifically inhibited by Compound E. Kidney International 2006 69, 1717-1721DOI: (10.1038/sj.ki.5000298) Copyright © 2006 International Society of Nephrology Terms and Conditions