Cell surface engineering of renal cell carcinoma with glycosylphosphatidylinositol-anchored TIMP-1 blocks TGF-β1 activation and reduces regulatory ID gene expression

Tissue inhibitor of metalloproteinase 1 (TIMP-1) controls matrix
metalloproteinase activity through 1:1 stoichiometric binding.
Human TIMP-1 fused to a glycosylphosphatidylinositol (GPI) anchor
(TIMP-1–GPI) shifts the activity of TIMP-1 from the extracellular
matrix to the cell surface. TIMP-1–GPI treated renal cell carcinoma
cells show increased apoptosis and reduced proliferation.
Transcriptomic profiling and regulatory pathway mapping were used
to identify the potential mechanisms driving these effects.
Significant changes in the DNA binding inhibitors, TGF-β1/SMAD and
BMP pathways resulted from TIMP-1–GPI treatment. These events were
linked to reduced TGF-β1 signaling mediated by inhibition of
proteolytic processing of latent TGF-β1 by TIMP-1–GPI.