Regulation of TIMPs through MMP-dependent cleavage

Authors

• S Shema
• Q Wei
• D Tillo
• M Wong
• EA Conner

Abstract

Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) are a broadly expressed family of matrisome proteins which are the primary regulators of metalloproteinase (MP) proteolytic activity. In addition to their canonically described functions, TIMPs display a broad range of MP-independent functional roles associated with proliferation, apoptosis, migration, and differentiation. MPs are endopeptidases that play an essential role in maintaining the extracellular matrix through proteolytic turnover; a balancing act maintained (in part) by the local MMP:TIMP ratio. Disturbances in the balance between MPs and TIMPs are associated with various disease states, including cancer, heart disease, arthritis, and cognitive dysfunctions. We describe a novel mode of MP-dependent regulation of TIMP function. We show that a molar excess of active matrix metalloproteinase 9 (aMMP9) can cleave TIMP proteins within their C-terminal domains, altering both the MP-dependent and -independent functions of TIMPs. MMP9 abundance and activity is often elevated during the pathogenesis of various diseases, and persistent MMP9 activity is frequently associated with worse prognoses. MMP9 is predominantly produced by stromal cell types such as fibroblasts and myeloid cells. Importantly, myeloid cell types often display low levels of TIMP production and thus may represent a functionally compelling source of TIMP-free MMP9. By stimulating myeloid cells into MMP9 secreting and activating subtypes, we interrogate the conditions that may enable TIMP cleavage in vivo. Investigation of the circumstances which modulate the balance between MPs and TIMPs may reveal new therapeutic opportunities in a range of disease models.

Scientific Focus Area: Cancer Biology

This page was last updated on Monday, September 25, 2023