The enzymatic activity of ADAM8 and ADAM9 is not regulated by TIMPs

By A. Amour, C. Knight, W. English, A. Webster, P. Slocombe, V. Knäuper, A. Docherty, J. Becherer, C. Blobel, Gillian Murphy. 2002

148 citations recorded by the source corpus.

The ADAM family of proteases are type I transmembrane proteins with both metalloproteinase and disintegrin containing extracellular domains. ADAMs are implicated in the proteolytic processing of membrane‐bound precursors and involved in modulating cell–cell and cell–matrix interactions. ADAM8 (MS2, CD156) has been identified in myeloid and B cells. In this report we demonstrate that soluble ADAM8 is an active metalloprotease in vitro and is able to hydrolyse myelin basic protein and a variety of peptide substrates based on the cleavage sites of membrane‐bound cytokines, growth factors and receptors which are known to be processed by metalloproteinases. Interestingly, although ADAM8 was inhibited by a number of peptide analogue hydroxamate inhibitors, it was not inhibited by the tissue inhibitors of metalloproteinases (TIMPs). We also demonstrate that the activity of recombinant soluble ADAM9 (meltrin‐γ, MDC9) lacks inhibition by the TIMPs, but can be inhibited by hydroxamate inhibitors. The lack of TIMP inhibition of ADAM8 and 9 contrasts with other membrane‐associated metalloproteinases characterised to date in this respect (ADAM10, 12, 17, and the membrane‐type metalloproteinases) which have been implicated in protein processing at the cell surface.

Subfields: Cancer Research, Immunology and Allergy, Oncology

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. R. Khalil
2. S. Zhong
3. D. Edwards

In Immunology and Allergy

1. C. Blobel
2. S. Zhong
3. R. Khalil

In Oncology

1. S. Zhong
2. C. Blobel
3. R. Khalil
4. D. Edwards
5. M. Handsley
6. C. Pennington

Citations in the corpus

• A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “Also, heparan sulfate glycosaminoglycans (GAGs) enhance TIMP-3 activity and therefore modulate its inhibitory effect on ADAMTS [59].”
• The ADAMs family of metalloproteases: multidomain proteins with multiple functions. (2003, background): “But not all ADAMs are sensitive to TIMP3; ADAM8 and ADAM9 processing of myelin basic protein is not inhibited by any TIMP (Amour et al. 2002).”
• The ADAM metalloproteinases (2008, background): “The catalytic domain of ADAM-10 is inhibited by both TIMP-1 and TIMP-3 (Amour et al., 2000) , whereas ADAM-8, -9 and -19 defy any pattern and are insensitive to TIMP inhibition (Amour et al., 2002; Chesneau et al., 2003) .”
• Metalloprotease‐disintegrin ADAM8: Expression analysis and targeted deletion in mice (2005, background): “The tissue inhibitor of matrix metalloproteinases (TIMP) -inhibitor profile of ADAM8 is like that of ADAM9 in that it is not inhibited by any of the known TIMP proteins (Amour et al., 2002; Schlomann et al., 2002).”
• Strategies to improve plasma half life time of peptide and protein drugs (2006, unknown): “B9 – Aprotinin, Benzamidine, Hydroxamates, o-Phenanthroline, phosporamidon, TIMP-1, TIMP-3 (Amour et al., 2002) 3.”