Review of: Metalloproteinase axes increase β-catenin signaling in primary mouse mammary epithelial cells lacking TIMP3

Abstract

of the original article:Multiple cancers exhibit mutations in b-catenin that lead to increased stability, altered localization or amplified activity. b-Catenin is situated at the junction between the cadherin-mediated cell adhesion and Wnt signaling pathways, and TIMP3 functions to alter b-catenin signaling. Here we demonstrate that primary mouse embryonic fibroblasts (MEFs) and mammary epithelial cells (MECs) deficient in Timp3 have increased b-catenin signaling. Functionally, the loss of TIMP3 exerted cell-type-specific effects, with Timp3 2/2 MEFs being more sensitive and Timp3 2/2 MECs more resistant to EGTA-induced cell detachment than the wild type. Timp3 2/2MECs had higher dephosphorylated b-catenin levels and increased b-catenin transcriptional activity as measured by TCF/LEF-responsive reporter assays. Real-time PCR analysis of b-catenin target genes in MEFs and MECs showed no alteration in Myc, decreased Ccnd1 (cyclin D1) and increased Mmp7 mRNA levels upon loss of TIMP3, with the latter occurring only in epithelial cells. Recombinant TIMP3 and synthetic metalloproteinase inhibitors reverted the increase in dephosphorylated b-catenin, decrease in Ccnd1 gene expression and increase in Mmp7 gene expression. Physiologically, Timp3 2/2 mammary glands displayed accelerated mammary ductal elongation during pubertal morphogenesis. Gain-of-function studies using slow-release TIMP-containing pellets revealed distinct effects of individual TIMPs on ductal morphogenesis. Recombinant TIMP1, TIMP3 and TIMP4 inhibited ductal elongation whereas TIMP2 promoted this process. ReviewThe Wnt signaling pathway is highly conserved throughout evolution, where it functions in Caenorhabditis elegans to mammals [1]. The pathway controls a number of biological responses including cell fate decisions, migration, morphogenesis, differentiation and stem cell renewal. There are three pathways that utilize the 20 known Wnt ligands and 10 frizzled (Fz) family of seven transmembrane receptors [2]. These include the canonical Wnt/bcatenin/Lef pathway where gene transcription is regulated through a transcriptional complex consisting of b-catenin and a member of the Tcf/Lef transcription factor family [3]. Binding of Wnt proteins to the Fz receptor with the co-receptor LRP5 or LRP6 leads to the intracellular activation of