Phosphorylation of pericyte FAK-Y861 affects tumour cell apoptosis and tumour blood vessel regression

Abstract

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that is overexpressed in many cancer types and in vivo studies have shown that vascular endothelial cell FAK expression and FAK-phosphorylation at tyrosine (Y) 397, and subsequently FAK-Y861, are important in tumour angiogenesis. Pericytes also play a vital role in regulating tumour blood vessel stabilisation, but the involvement of pericyte FAK-Y397 and FAK-Y861 phosphorylation in tumour blood vessels is unknown. Using PdgfrbCre+;FAK WT/WT , PdgfrbCre+;FAK Y397F/Y397F and PdgfrbCre+;FAK Y861F/Y861F mice, our data demonstrate that tumour growth, tumour blood vessel density, blood vessel perfusion and pericyte coverage were affected only in late stage tumours in PdgfrbCre+;FAK Y861F/Y861F but not PdgfrbCre+;FAK Y397F/Y397F mice. Further examination indicates a dual role for pericyte FAK-Y861 phosphorylation in the regulation of tumour vessel regression and also in the control of a pericyte derived 'pericrine' signals that influence apoptosis in cancer cells. Overall this study identifies the role of pericyte FAK-Y861 in the regulation of tumour vessel regression and tumour growth control and that non-phosphorylatable FAK-Y861F in pericytes reduces tumour growth and blood vessel density.

The Adhesome Network: Key Components Shaping the Tumour Stroma

“…As in ECs, pericyte FAK phosphorylation appears to have distinct roles in tumour growth and angiogenesis. Whereas phosphorylation of mural FAK at Y397 does not seem to affect angiogenesis and tumour growth, the phosphorylation at Y861 is important for blocking vessel regression and enhancing tumour survival [ 20 ].…”