title: The isolated N-terminal domains of TIMP-1 and TIMP-3 are insufficient for ADAM10 inhibition.
abstract: ADAM (a disintegrin and metalloproteinase) 10 is a key member of the ADAM family of disintegrin and metalloproteinases which process membrane-associated proteins to soluble forms in a process known as 'shedding'. Among the major targets of ADAM10 are Notch, EphrinA2 and CD44. In many cell-based studies of shedding, the activity of ADAM10 appears to overlap with that of ADAM17, which has a similar active-site topology relative to the other proteolytically active ADAMs. The tissue inhibitors of metalloproteinases, TIMPs, have proved useful in the study of ADAM function, since TIMP-1 inhibits ADAM10, but not ADAM17; however, both enzymes are inhibited by TIMP-3. In the present study, we show that, in comparison with ADAM17 and the MMPs (matrix metalloproteinases), the N-terminal domains of TIMPs alone are insufficient for the inhibition of ADAM10. This knowledge could form the basis for the design of directed inhibitors against different metalloproteinases.
authors.affiliation: Department of Oncology, Cambridge University, Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, Cambridge CB2 0RE, UK.
authors.forename: Magdalini
authors.initials: M
authors.lastname: Rapti
authors.forename: Susan J
authors.initials: SJ
authors.lastname: Atkinson
authors.forename: Meng-Huee
authors.initials: MH
authors.lastname: Lee
authors.forename: Andrew
authors.initials: A
authors.lastname: Trim
authors.forename: Marcia
authors.initials: M
authors.lastname: Moss
authors.forename: Gillian
authors.initials: G
authors.lastname: Murphy
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D011480:Protease Inhibitors / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D012995:Solubility; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*
chemical_list: D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D019715:Tissue Inhibitor of Metalloproteinase-1; D019717:Tissue Inhibitor of Metalloproteinase-3; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human