HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boutet, P. Articles by Valés-Gómez, M. Search for Related Content PubMed PubMed Citation Articles by Boutet, P. Articles by Valés-Gómez, M.

Cutting Edge: The Metalloproteinase ADAM17/TNF--Converting Enzyme Regulates Proteolytic Shedding of the MHC Class I-Related Chain B Protein¹

Philippe Boutet^2,*, Sonia Agüera-González^2,*, Susan Atkinson, Caroline J. Pennington, Dylan R. Edwards, Gillian Murphy, Hugh T. Reyburn^* and Mar Valés-Gómez^3,*

^* Department of Pathology, University of Cambridge, Cambridge, United Kingdom; Department of Oncology, Cancer Research U.K., Cambridge Research Institute, Cambridge University, Cambridge, United Kingdom; and School of Biological Sciences, University of East Anglia, Norwich, United Kingdom

MHC class I-related chain (MIC) A/B are transmembrane proteins expressed in pathological conditions that are ligands for the activating receptor NKG2D found on cytotoxic lymphocytes. Soluble NKG2D ligands are detected in sera of patients suffering from multiple types of cancer where they are associated with reduced levels of receptor expression and compromised function of NK and CTLs. In this study, we report the identification of a metalloproteinase involved in the cleavage process of MIC; inhibition and knockdown of ADAM17/TACE blocks the shedding of these proteins. Strikingly, the recruitment of both enzyme and substrate to detergent-resistant membrane microdomains is crucial for efficient proteolysis. These findings provide a novel insight into the molecular mechanisms of MIC shedding.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Leukaemia Research Fund, The Newton Trust and the Medical Research Council. S.A.-G. is a recipient of a studentship from the Fundación Caja Madrid. D.R.E. and G.M. acknowledge support from the European Union Framework Programme 6 Cancer Degradome Project LSHC-CT-2003-503297.

² P.B. and S.A.-G. contributed equally to the present work.

³ Address correspondence and reprint requests to Dr. Mar Valés-Gómez, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, U.K. E-mail address: mv231{at}cam.ac.uk

⁴ Abbreviations used in this paper: MIC, MHC class I-related chain; ADAM, a disintegrin and metalloproteinase; DRM, detergent-resistant membrane microdomain; MMP, matrix metalloproteinase; siRNA, small interfering RNA; sMIC, soluble MIC; TACE, TNF--converting enzyme; TIMP, tissue inhibitor of metalloproteinase.

⁵ The online version of this article contains supplemental material.

This article has been cited by other articles:

				K. Kohga, T. Takehara, T. Tatsumi, T. Miyagi, H. Ishida, K. Ohkawa, T. Kanto, N. Hiramatsu, and N. Hayashi Anticancer Chemotherapy Inhibits MHC Class I-Related Chain A Ectodomain Shedding by Downregulating ADAM10 Expression in Hepatocellular Carcinoma Cancer Res., October 15, 2009; 69(20): 8050 - 8057. [Abstract] [Full Text] [PDF]

				A. Paschen, A. Sucker, B. Hill, I. Moll, M. Zapatka, X. D. Nguyen, G. C. Sim, I. Gutmann, J. Hassel, J. C. Becker, et al. Differential Clinical Significance of Individual NKG2D Ligands in Melanoma: Soluble ULBP2 as an Indicator of Poor Prognosis Superior to S100B Clin. Cancer Res., August 15, 2009; 15(16): 5208 - 5215. [Abstract] [Full Text] [PDF]