Extracellular Phosphorylation of TIMP-2 by Secreted c-Src Tyrosine Kinase Controls MMP-2 Activity

• Published in: iScience Vol. 1; pp. 87 - 96
• Main Authors: Sánchez-Pozo, Javier, Baker-Williams, Alexander J., Woodford, Mark R., Bullard, Renee, Wei, Beiyang, Mollapour, Mehdi, Stetler-Stevenson, William G., Bratslavsky, Gennady, Bourboulia, Dimitra
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.03.2018; Elsevier
• Subjects: Biochemistry; Enzymology; Molecular Biology; Molecular Biology; Enzymology; Biochemistry
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2018.02.004

The tissue inhibitor of metalloproteinases 2 (TIMP-2) is a specific endogenous inhibitor of matrix metalloproteinase 2 (MMP-2), which is a key enzyme that degrades the extracellular matrix and promotes tumor cell invasion. Although the TIMP-2:MMP-2 complex controls proteolysis, the signaling mechanism by which the two proteins associate in the extracellular space remains unidentified. Here we report that TIMP-2 is phosphorylated outside the cell by secreted c-Src tyrosine kinase. As a consequence, phosphorylation at Y90 significantly enhances TIMP-2 potency as an MMP-2 inhibitor and weakens the catalytic action of the active enzyme. TIMP-2 phosphorylation also appears to be essential for its interaction with the latent enzyme proMMP-2 in vivo. Absence of the kinase or non-phosphorylatable Y90 abolishes TIMP-2 binding to the latent enzyme, ultimately hampering proMMP-2 activation. Together, TIMP-2 phosphorylation by secreted c-Src represents a critical extracellular regulatory mechanism that controls the proteolytic function of MMP-2. [Display omitted] •c-Src tyrosine kinase phosphorylates TIMP-2•Secreted c-Src phosphorylates TIMP-2 extracellularly•TIMP-2 Y90 phosphorylation promotes extracellular interaction with proMMP-2•Tyrosine phosphorylation of TIMP-2 regulates proMMP-2 processing and MMP-2 activity Biochemistry; Enzymology; Molecular Biology