Fine Tuning Cell Migration by a Disintegrin and Metalloproteinases

Figure 1

Catalytic and noncatalytic functions of ADAM proteases facilitating cell migration. ADAM proteases interfere with distinct steps of cell migration via a number different effector molecules. This involves proteolytic cleavage or nonproteolytic interactions of the proteases. ADAMs consist of a C-terminal cytoplasmic tail (CC) followed by a transmembrane domain (TM), an EGF-like domain (EL), a cysteine-rich domain (CR), and a disintegrin domain (D) and an extracellular metalloproteinase domain (MP) (ADAM). ADAM proteases cleave transmembrane surface molecules close to the plasma membrane, a process called shedding, requiring a zinc atom in the active site of the metalloproteinase domain (I). This results in the release of a soluble ectodomain and the production of a cell-associated fragment consisting of the transmembrane and cytoplasmic domain. The remaining fragment can undergo further regulated intramembrane proteolysis by γ-secretase (II) at last functioning as transcription factor (e.g., Notch). ADAM activity can be regulated by activation of a precursor protein (e.g., pro-MMP9). The released ectodomain may function either as agonist like the chemokine CXCL16 and the ErbB ligands HB-EGF and neuregulin or as antagonist like soluble JAM-A or RAGE (III). The release of ErbB ligands leads to transactivation of ErbB receptors in cis and trans (IV). The inactivation of ligands (i.e., adhesion molecules (AM)) can lead to the detachment of bound receptor complexes and attached cells (i.e., L-selectin, MAC-1) (V). The cleavage of junction molecules (JM, i.e., cadherins) results in changes of permeability (VI), facilitating the transmigration of inflammatory cells, the invasion of cancer cells, and the dissemination resulting in metastasis and angiogenic processes (VII). The permeability is further regulated by ECM degradation, by either direct action of ADAM proteases (i.e., ADAM9) or the regulation of MMPs (VIII). With their disintegrin-like domain, ADAMs can directly interact with adhesion molecules and ECM proteins (IX). The integrin (indicated by ) interaction/activation results in cytoskeletal rearrangement, focal adhesion formation, and podosome extension (X). Integrin, ADAM activation, and ErbB receptor transactivation result in different signaling pathways including the activation of Rho, Rac, FAK, PI3K, AKT, p38, and ERK, all further regulating ADAM and integrin activity as well as gene expression (XI). The exact mechanism of cell migration can differ between rapidly migrating leukocytes and tissue cells. However, the involved surface molecules, the signal transduction pathways, and the molecular machinery show a considerable degree of overlap for the action of ADAM proteases in inflammatory cell recruitment, angiogenesis, reepithelialization, cancer cell detachment and adhesion, and the intra- and extravasation during metastasis.