Table 2.

MMP-independent functions of TIMP-2

Affected protein	Effect on function	Mechanism	Reference
VEGF-A	Reduced human microvascular endothelial cell (hMVECs) growth. Reduced human umbilical vein endothelial cell migration, proliferation, and tubular formation	TIMP-2 N-terminus binds to α3β1 integrin receptor. TIMP-2 peptide 9 inhibits VEGF-A, resulting in increased cAMP/PKA levels and the induction of p27Kip1	[27–29]
VEGFR2 and FGFR1	Decreased endothelial cell proliferation and angiogenesis	TIMP-2 binds to the α3β1 integrin receptor; SHP-1 inactivates/dephosphorylates VEGFR2 and FGFR1	[20, 27, 30]
VEGF-A	Decreased vascular permeability	Inhibition of VEGF-A leads to increased cAMP levels. Increasing VE-cadherin association with the actin cytoskeleton, increasing cell-cell contacts	[31]
Decreased ERK and AKT phosphorylation	Inhibition of endothelial cell proliferation and angiogenesis	TIMP-2 binding and inhibition of IGF-R1 via Loop 6, C-terminus	[32]
RECK and p27Kip1	Suppression of endothelial cell migration	Transcriptional regulation	[33, 34]
MDSCs	Reduction of angiogenesis and A549 tumor growth	TIMP-2 inhibition of the recruitment of MDSCs	[35]
EGFR	Decreased EGFR activation and growth suppression on A549 cells	Binding of TIMP-2 to increase cytosolic cAMP levels, preventing SHP-1 from dissociating EGFR, leading to hypophosphorylation and inactivation of EGFR	[36]
FAK and AKT, Decreased FAK and AKT phosphorylation	A549 cell migration and invasion. In A549 xenograft tissues by immunohistochemistry	Not determined	[37]
EFEMP1, Fibronectin, E-cadherin, IGF-R1, SEMA-3A, ANGPT1	A549 lung cancer xenografts Inhibition of tumor growth in vivo	Transcriptional regulation	[38]
ABCB1, ABCG2, AKR1C1	Decreased expression in side population in A549 cells, increased chemosensitivity	Transcriptional regulation	[39, 30]