In this section, we consider signaling pathways activated by protein cleavage in an extracellular space—often at the surface of the cell—generally by members of the matrix metalloprotease (MMP) family and more specifically by the subclass of transmembrane ADAMs (a-disintegrin-and-metalloproteases; a disintegrin is a conserved protein domain that binds integrins and disrupts cell-matrix interactions—see Chapter 20). In the Notch/Delta pathway, for instance, ADAM cleavage of the extracellular part of the Notch receptor is followed by Notch cleavage within the plasma membrane by a different protease, releasing the cytosolic domain that functions as a transcription factor. This pathway determines the fates of many types of cells during development.

Earlier in the chapter, we saw that multiple growth factors signal through receptor tyrosine kinases. Many such growth factors, including members of the epidermal growth factor (EGF) family, are made as membrane-spanning precursors and can signal adjacent cells by binding to EGF receptors on their surfaces. But cleavage of these proteins by matrix metalloproteases releases the active growth factors into the extracellular medium, allowing them to signal cells much farther away, and even to the releasing cells themselves (autocrine signaling). Since this process involves a form of proteolytic cleavage similar to that which occurs in the Notch/Delta pathway, we consider it here as well. Inappropriate MMP cleavage of a membrane-spanning protein expressed in nerve cells has been implicated in the pathology of Alzheimer’s disease, and we discuss this process as well.

Regulated protein cleavage is also used in some intracellular signaling pathways. Thus we conclude our discussion by describing one such pathway: the intramembrane cleavage of a transcription factor precursor within the Golgi membrane in response to low cholesterol levels. This pathway is essential for maintaining the proper balance of cholesterol and phospholipids for constructing cell membranes (see Chapter 7).