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

Javier Sánchez-Pozo1, Alexander J Baker-Williams1, Mark R Woodford1

  • 1Department of Urology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Department of Biochemistry and Molecular Biology, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA; Upstate Cancer Center, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA.

Iscience
|September 20, 2018
PubMed

Insights

Phosphorylation of tissue inhibitor of metalloproteinases 2 (TIMP-2) by secreted c-Src kinase enhances its MMP-2 inhibition. This phosphorylation is crucial for TIMP-2 binding to latent MMP-2, controlling matrix metalloproteinase 2 activation.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Research

Background:

  • Matrix metalloproteinase 2 (MMP-2) degrades the extracellular matrix, promoting tumor invasion.
  • Tissue inhibitor of metalloproteinases 2 (TIMP-2) specifically inhibits MMP-2, but its extracellular interaction mechanism was unknown.
  • Understanding TIMP-2:MMP-2 complex regulation is key to controlling proteolysis in cancer.

Purpose of the Study:

  • To identify the signaling mechanism of TIMP-2 and MMP-2 association in the extracellular space.
  • To investigate the role of TIMP-2 phosphorylation in its inhibitory function and interaction with MMP-2.
  • To elucidate the upstream kinase responsible for TIMP-2 extracellular modification.

Main Methods:

  • Investigated extracellular phosphorylation of TIMP-2 using secreted c-Src tyrosine kinase.
  • Assessed the impact of Y90 phosphorylation on TIMP-2's inhibitory potency against MMP-2.
  • Examined TIMP-2 binding to latent proMMP-2 in the presence and absence of c-Src kinase or Y90 phosphorylation.

Main Results:

  • TIMP-2 is phosphorylated extracellularly by secreted c-Src tyrosine kinase at Y90.
  • Phosphorylation at Y90 significantly enhances TIMP-2's inhibitory activity against active MMP-2.
  • TIMP-2 phosphorylation at Y90 is essential for binding to latent proMMP-2, thereby regulating proMMP-2 activation.

Conclusions:

  • Extracellular phosphorylation of TIMP-2 by c-Src is a critical regulatory mechanism.
  • This phosphorylation controls MMP-2 proteolytic activity and activation.
  • TIMP-2 phosphorylation represents a novel target for modulating MMP-2 function in disease.
Keywords:
BiochemistryEnzymologyMolecular Biology

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