The hemopexin domain of MMP3 is responsible for mammary epithelial invasion and morphogenesis through extracellular interaction with HSP90 beta

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Correia, AL (Author) Other; Mori, H (Author) Other; Chen, EI (Author) Other; Fernando Schmitt (Author) FMUP; Bissell, MJ (Author) Other

Journal

Title: GENES & DEVELOPMENT

Vol. 27

Pages: 805-817

ISSN: 0890-9369

Indexing

ISI Web of Knowledge - 72 Citations

Scopus - 74 Citations

Other information

Authenticus ID: P-005-1YT

DOI: 10.1101/gad.211383.112

Abstract (EN): Matrix metalloproteinases (MMPs) are crucial mediators in sculpting tissue architecture and are required for many physiological and pathological processes. MMP3 has been shown to regulate branching morphogenesis in the mammary gland. Ectopic expression of proteolytically active MMP3 in mouse mammary epithelia triggers supernumerary lateral branching and, eventually, tumors. Using a three-dimensional collagen-I (Col-1) gel assay that simulates epithelial invasion and branching, we show that it is the hemopexin domain that directs these processes. Using three different engineered constructs containing a variation on MMP3 structural domains, we confirmed the importance of the hemopexin domain also in primary organoids of the mammary gland. A proteomic screen of MMP3-binding partners surprisingly revealed that the intracellular chaperone heat-shock protein 90 beta (HSP90 beta) is present extracellularly, and its interaction with the hemopexin domain of MMP3 is critical for invasion. Blocking of HSP90 beta with inhibitory antibodies added to the medium abolished invasion and branching. These findings shift the focus from the proteolytic activity of MMP3 as the central player to its hemopexin domain and add a new dimension to HSP90 beta's functions by revealing a hitherto undescribed mechanism of MMP3 regulation. Our data also may shed light on the failure of strategies to use MMP inhibitors in cancer treatment and other related disorders.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13