title: New insight into the role of MMP14 in metabolic balance.
abstract: Membrane-anchored matrix metalloproteinase 14 (MMP14) is involved broadly in organ development through both its proteolytic and signal-transducing functions. Knockout of Mmp14 (KO) in mice results in a dramatic reduction of body size and wasting followed by premature death, the mechanism of which is poorly understood. Since the mammary gland develops after birth and is thus dependent for its functional progression on systemic and local cues, we chose it as an organ model for understanding why KO mice fail to thrive. A global analysis of the mammary glands' proteome in the wild type (WT) and KO mice provided insight into an unexpected role of MMP14 in maintaining metabolism and homeostasis. We performed mass spectrometry and quantitative proteomics to determine the protein signatures of mammary glands from 7 to 11 days old WT and KO mice and found that KO rudiments had a significantly higher level of rate-limiting enzymes involved in catabolic pathways. Glycogen and lipid levels in KO rudiments were reduced, and the circulating levels of triglycerides and glucose were lower. Analysis of the ultrastructure of mammary glands imaged by electron microscopy revealed a significant increase in autophagy signatures in KO mice. Finally, Mmp14 silenced mammary epithelial cells displayed enhanced autophagy. Applied to a systemic level, these findings indicate that MMP14 is a crucial regulator of tissue homeostasis. If operative on a systemic level, these findings could explain how Mmp14KO litter fail to thrive due to disorder in metabolism.
authors.affiliation: Department of Pathology, Center for Comparative Medicine, University of California,Davis,CA,USA; Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory,Berkeley,CA,USA.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Mori
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory,Berkeley,CA,USA; Calcutta Medical College, University of Calcutta, Calcutta, India.
authors.forename: Ramray
authors.initials: R
authors.lastname: Bhat
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory,Berkeley,CA,USA; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo,São Paulo,Brazil.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bruni-Cardoso
authors.affiliation: Department of Pharmacology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center , New York , NY , USA.
authors.forename: Emily I
authors.initials: EI
authors.lastname: Chen
authors.affiliation: Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Jorgens
authors.affiliation: Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Kester
authors.initials: K
authors.lastname: Coutinho
authors.affiliation: Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Louie
authors.affiliation: Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Benjamin Ben
authors.initials: BB
authors.lastname: Bowen
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Inman
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Tecca
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Sabine
authors.initials: S
authors.lastname: Becker-Weimann
authors.affiliation: Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Trent
authors.initials: T
authors.lastname: Northen
authors.affiliation: Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.affiliation: Department of Pathology, Center for Comparative Medicine, University of California, Davis, CA, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.affiliation: Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Manfred
authors.initials: M
authors.lastname: Auer
authors.affiliation: Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors.forename: Mina J
authors.initials: MJ
authors.lastname: Bissell
keywords: Autophagy; Energy metabolism; Glucose; Glycogen; Homeostasis; Lipids; Mammary gland; Matrix metalloproteinase 14; Mmp14KO mouse; Triglycerides