Table 2 MMP-independent functions of TIMP-2

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 p27^Kip1

[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 p27^Kip1

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]