Journal article

An activated form of ADAM10 is tumor selective and regulates cancer stem-like cells and tumor growth

Lakmali Atapattu, Nayanendu Saha, Chanly Chheang, Moritz F Eissman, Kai Xu, Mary E Vail, Linda Hii, Carmen Llerena, Zhanqi Liu, Katja Horvay, Helen E Abud, Ulrike Kusebauch, Robert L Moritz, Bi-Sen Ding, Zhongwei Cao, Shahin Rafii, Matthias Ernst, Andrew M Scott, Dimitar B Nikolov, Martin Lackmann Show all

Journal of Experimental Medicine | ROCKEFELLER UNIV PRESS | Published : 2016

Abstract

The transmembrane metalloprotease ADAM10 sheds a range of cell surface proteins, including ligands and receptors of the Notch, Eph, and erbB families, thereby activating signaling pathways critical for tumor initiation and maintenance. ADAM10 is thus a promising therapeutic target. Although widely expressed, its activity is normally tightly regulated. We now report prevalence of an active form of ADAM10 in tumors compared with normal tissues, in mouse models and humans, identified by our conformation-specific antibody mAb 8C7. Structure/function experiments indicate mAb 8C7 binds an active conformation dependent on disulfide isomerization and oxidative conditions, common in tumors. Moreover,..

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Grants

Awarded by National Health and Medical Research Council (NHM RC), Australia


Awarded by National Institutes of Health


Awarded by National Institute of General Medical Sciences from the National Institutes of Health


Awarded by US DOE


Awarded by NATIONAL CANCER INSTITUTE


Awarded by NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES


Awarded by NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE


Funding Acknowledgements

This work was supported by National Health and Medical Research Council (NHM RC), Australia (grants 384242, 1067609, and 1093304; fellowships to P.W. Janes [384285], M. Lackmann [1003908], M. Ernst [1079257], and A.M. Scott [1084178]; and scholarship to L. Atapattu [1017654]) and by funds from the Operational Infrastructure Support Program provided by the Victorian Government, Australia. Additional funding included an award to D.B. Nikolov from The Experimental Therapeutics Center of Memorial Sloan-Kettering, support from Mr. William H. and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, and National Institutes of Health grants R21CA185930 and R01 NS03848 (to D.B. Nikolov). x-ray diffraction experiments were conducted remotely at the Advanced Photon Source on the Northeastern Collaborative Access Team beamlines ID24, which are supported by a grant from the National Institute of General Medical Sciences (P41 GM103403) from the National Institutes of Health. Use of the Advanced Photon Source, an Office of Science User Facility operated for the US Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the US DOE under contract no. DE-AC02-06CH11357.