Matrix Metalloproteases Catalyze Cleavage of Many Signaling Proteins from the Cell Surface

Many signaling molecules are synthesized as transmembrane proteins whose signal domain extends into the extracellular space. Such signaling proteins, like Delta described above, are often biologically active but can signal only by binding to receptors on adjacent cells. However, many growth factors and other protein signals are synthesized as transmembrane precursors whose cleavage releases the soluble, active signaling molecule into the extracellular space. This cleavage is often carried out by ADAMs. The human genome encodes 21 matrix metalloproteases in the ADAM family, but only 12 are known to be catalytically active; the rest may function as disintegrins. Many ADAMs are involved in cleaving the precursors of signaling proteins just outside their transmembrane segment.

Medically important examples of the regulated cleavage of precursors of signaling proteins are members of the EGF family, including EGF, HB-EGF, TGF-α, NRG1, and NRG2 (see Figure 16-17). Increased activity of one or more ADAMs, which is seen in many cancers, can promote cancer development in three ways. First, heightened ADAM activity can lead to high levels of extracellular EGF-family growth factors that stimulate the secreting cells (autocrine signaling) or adjacent cells (paracrine signaling) to proliferate inappropriately. Second, by destroying components of the extracellular matrix, increased ADAM activity is thought to facilitate metastasis, the movement of tumor cells to other sites in the body (see Chapter 24). Third, following metalloprotease cleavage of the extracellular domain, cleavage by γ-secretase releases the cytosolic fragment of these precursor proteins, in a manner similar to the release of the Notch intracellular domain. Several of these protein fragments migrate into the nucleus, where, like the Notch intracellular domain, they stimulate the transcription of growth-promoting genes.

ADAM proteases also are an important factor in heart disease. As we learned in the last chapter, epinephrine (adrenaline) stimulation of β-adrenergic receptors in heart muscle causes glycogenolysis and an increase in the rate of muscle contraction. Prolonged treatment of heart muscle cells with epinephrine, however, leads to activation of an ADAM by an unknown mechanism. This matrix metalloprotease cleaves the transmembrane precursor of HB-EGF. The released HB-EGF then binds to EGF receptors on heart muscle cells and stimulates their inappropriate growth. This excessive proliferation can lead to an enlarged but weakened heart—a condition known as cardiac hypertrophy, which may cause early death.