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Chemical Tools for Selective Activity Profiling of Endogenously Expressed MMP-14 in Multicellular Models.

Abstract：

:Matrix metalloproteases (MMPs) are a large family of zinc-dependent endopeptidases involved in a diverse set of physiological and pathological processes, most notably in cancer. Current methods for imaging and quantifying MMP activity lack sufficient selectivity and spatiotemporal resolution to allow studies of specific MMP function in vivo. Previously, we reported a strategy for selective targeting of MMPs by engineering a functionally silent cysteine mutation that enables highly specific covalent modification by a designed activity-based probe. Here, we describe the translation of that technology into a mouse model of breast cancer and subsequent demonstration of the utility of the approach for studies of MMP-14 activation in the tumor microenvironment. Using this approach, we find that MMP-14 is active in late stage tumors and is predominantly associated with stromal cell populations that have been activated by specific signaling molecules (e.g., TGFβ) produced by tumor cells. Our data demonstrate the applicability of this approach for studies of MMP function in whole organisms and identify important regulatory mechanisms for MMP-14 activity in the tumor microenvironment.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Amara N,Tholen M,Bogyo M

doi

10.1021/acschembio.8b00562

subject

Has Abstract

pub_date

2018-09-21 00:00:00

pages

2645-2654

issue

9

eissn

1554-8929

issn

1554-8937

journal_volume

13

pub_type

杂志文章

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