Physiologic and Pathologic Events Mediated by Intramembranous and Juxtamembranous Proteolysis

Science's STKE  04 Mar 2003:
Vol. 2003, Issue 172, pp. re4
DOI: 10.1126/stke.2003.172.re4

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This STKE review describes one of the more recently recognized ways in which cells transmit signals across lipid bilayers--through the action of proteases on proteins that span the membrane. In some cases, a protease cleaves a signaling protein within its membrane-spanning domain to release either the target protein's cytoplasmic domain or its extracellular domain. Once cleaved and released from the membrane, these soluble domains can transmit a signal either locally or at some distance from the site of cleavage. This type of proteolytic cleavage is referred to as intramembranous proteolysis (IP). In a second type of proteolytic cleavage of transmembrane proteins that mediates cell signaling, the target protein is cleaved at a site close to, but not within, the transmembrane domain. This type of proteolysis is called juxtamembranous proteolysis (JP). JP and IP can sequentially mediate signaling events, with the combined action of these two cleavages resulting in transmission of signals within the cell. Several important cellular signaling pathways are regulated by both JP and IP, for example, regulation of the transcription of enzymes that control cholesterol synthesis; developmental regulation of cell differentiation; and growth regulation in somatic cells. IP and JP also have important roles in certain diseases, such as Alzheimer's disease. Because some of the proteases mediating IP and JP can be targeted by small drug-like molecules, inhibitors targeting these proteases are likely to alter both physiologic and pathologic events triggered by IP and JP.