A Role for Matrix Metalloproteinases in Regulating Mammary Stem Cell Function Via the Wnt Signaling Pathway

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Jul 23

PMID 23871604

Citations 73

Authors

Kai Kessenbrock

Gerrit J P Dijkgraaf

Devon A Lawson

Laurie E Littlepage

Payam Shahi

Ursula Pieper

Zena Werb

Affiliations

Soon will be listed here.

Abstract

The microenvironment provides cues that control the behavior of epithelial stem and progenitor cells. Here, we identify matrix metalloproteinase-3 (MMP3) as a regulator of Wnt signaling and mammary stem cell (MaSC) activity. We show that MMP3 overexpression promotes hyperplastic epithelial growth, surprisingly, in a nonproteolytic manner via its hemopexin (HPX) domain. We demonstrate that MMP3-HPX specifically binds and inactivates Wnt5b, a noncanonical Wnt ligand that inhibits canonical Wnt signaling and mammary epithelial outgrowth in vivo. Indeed, transplants overexpressing MMP3 display increased canonical Wnt signaling, demonstrating that MMP3 is an extracellular regulator of the Wnt signaling pathway. MMP3-deficient mice exhibit decreased MaSC populations and diminished mammary-reconstituting activity, whereas MMP3 overexpression elevates MaSC function, indicating that MMP3 is necessary for the maintenance of MaSCs. Our study reveals a mechanism by a microenvironmental protease that regulates Wnt signaling and impacts adult epithelial stem cell function.

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