Abstract
Vascular endothelial growth factor (VEGF) is a major angiogenic factor that triggers formation of new vessels under physiological and pathological conditions. However, the mechanisms that limit the VEGF responses in target cells and hence prevent excessive and harmful angiogenesis are not well understood. Here, our objective was to study whether T-cell protein tyrosine phosphatase (TCPTP, also known as PTN2), which we found to be expressed in human endothelial cells, could alter VEGF signalling by controlling phosphorylation of VEGFR2. We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. We found that TCPTP activity is induced upon integrin-mediated binding of endothelial cells to collagen matrix. TCPTP activation was also induced by using cell-permeable peptides from the cytoplasmic tail of the collagen-binding integrin alpha1. Controlled activation of TCPTP results in inhibition of VEGF-triggered endothelial cell proliferation, angiogenic sprouting, chemokinesis and chemotaxis. We conclude that matrix-controlled TCPTP phosphatase activity can inhibit VEGFR2 signalling, and the growth, migration and differentiation of human endothelial cells.
Highlights
Vascular endothelial growth factor (VEGF) is a major growth factor for endothelial cells
We conclude that matrixcontrolled T-cell protein tyrosine phosphatase (TCPTP) phosphatase activity can inhibit VEGFR2 signalling, and the growth, migration and differentiation of human endothelial cells
TCPTP is present in human endothelial cells We hypothesized that human endothelial cells might express TCPTP and that the collagen-binding integrin α1 could regulate the activity of TCPTP in these cells
Summary
VEGF is a major growth factor for endothelial cells. It regulates endothelial cell function in the formation of new blood vessels both during development and in adults (e.g. during wound healing and in proliferative diseases such as cancer) (Coultas et al, 2005). VEGFR2 appears to be the main mediator of VEGF-induced endothelial proliferation, survival, migration, tubular morphogenesis and sprouting in adults (Ferrara et al, 2003). Upon binding of VEGF, the receptors dimerize, become autophosphorylated, and recruit signal-transduction molecules such as PLC, PI3K and Ras (Olsson et al, 2006; Kerbel, 2008; Siekmann et al, 2008). Negative regulation of VEGFR2 signalling is important in limiting the response of VEGF in target cells. Inhibition of neovascularization is a promising new way of treating diseases such as cancer and certain retinopathies (Carmeliet, 2005)
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