Key Concepts of Section 16.7

Key Concepts of Section 16.7

Signaling Pathways Controlled by Protein Cleavage: Notch/Delta, SREBP, and Alzheimer’s Disease

  • Many important growth factors and other signaling proteins such as EGFs are synthesized as transmembrane proteins; regulated cleavage of the precursor near the plasma membrane by members of the matrix metalloprotease (MMP) family releases the active molecule into the extracellular space to signal distant cells.

  • On binding to its ligand, Delta, on the surface of an adjacent cell, the receptor Notch protein undergoes two proteolytic cleavages (see Figure 16-36). The released Notch cytosolic segment then translocates into the nucleus and modulates transcription of target genes critical in determining cell fate during development.

  • Cleavage of membrane-bound precursors of members of the EGF family of signaling molecules is catalyzed by ADAM metalloproteases. Inappropriate cleavage of these precursors can result in abnormal cell proliferation, potentially leading to cancer, cardiac hypertrophy, and other diseases.

  • γ-Secretase, which catalyzes the regulated intramembrane proteolysis of Notch, also participates in the cleavage of amyloid precursor protein (APP) into a peptide that forms plaques characteristic of Alzheimer’s disease (see Figure 16-37).

  • In the insig-1(2)/SCAP/SREBP pathway, the active nSREBP transcription factor is released from the Golgi membrane by intramembrane proteolysis when cellular cholesterol is low (see Figure 16-38). It then stimulates the expression of genes encoding proteins that function in cholesterol biosynthesis (e.g., HMG-CoA reductase) and cellular import of cholesterol (e.g., LDL receptor). When cholesterol is high, SREBP is retained in the ER membrane complexed with insig-1(2) and SCAP (see Figure 16-38).