Figure 4.

TIMP2 signaling though α3β1 integrin.

In a mechanism that was identified in endothelial cells and fibroblasts, TIMP2 can bind to α3β1 integrin at the cell surface. A key mediator of the downstream effects of TIMP2 binding to α3β1 integrin is the activation of cytosolic tyrosine phosphatase SHP-1. Downstream activity of SHP-1 promotes cell cycle arrest through upregulation and enhanced nuclear localization of p27^KIP1. TIMP2 treatment also results in an increase in the expression of the membrane-anchored metalloproteinase inhibitor RECK via Rap1 mediated signaling, leading to reduced cell migration/invasion. Created with BioRender.com.