Abstract
ADAM12 is one of only a few ADAMs that exist in two forms: the prototype transmembrane form, ADAM12-L, and an alternatively spliced secreted form, ADAM12-S. ADAM 12 is an active metalloprotease, and substrates include IGFPB-3 and -5 and membrane-anchored pro-growth factor HB-EGF. ADAM12 interacts with integrin and syndecan adhesion receptors via the disintegrin and cysteine-rich domains, and influences cell shape, cytoskeleton, and the organization of the extracellular matrix. ADAM12 is expressed mainly during development and differentiation, in remodelling tissues, and in fast growing tissues such as placenta and malignant tumors. These key features of ADAM12 may have direct implications for clinical medicine. Mice deficient in ADAM12 are born fully developed, but approximately 30% of the null mice die within 1 week of birth. Surviving adult null mice appear phenotypically normal, but have reduced amounts of adipose and muscle tissue, in accord with a role for ADAM12 in myogenesis and adipogenesis. This role is further supported by ADAM12 promoting adipogenesis and myogenesis in wild type and dystrophin-deficient mdx mice. We are left with many questions about the function of ADAM12 and in particular about the molecular mechanisms such as 1) why is the prodomain still attached to ADAM12 after cleavage; 2) what are the physiological substrates of ADAM12; we know a few but probably not all; 3) how is the disintegrin and cysteine-rich domain regulating syndecans and integrins; we know it binds but we need to know the cause and the effect; and 4) what are the physiological ligands of the cytoplasmic domain, and importantly, when and where in the cell do they bind. In conclusion, ADAM12 appears to exert many cellular activities which may be strictly regulated in a cell type and context-specific manner.
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Wewer, U.M., Albrechtsen, R., Engvall, E. (2005). ADAM12. In: Hooper, N.M., Lendeckel, U. (eds) The ADAM Family of Proteases. Proteases in Biology and Disease, vol 4. Springer, Boston, MA. https://doi.org/10.1007/0-387-25151-0_6
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