| First Author | Kastana P | Year | 2023 |
| Journal | Int J Cancer | Volume | 153 |
| Issue | 5 | Pages | 1051-1066 |
| PubMed ID | 37260355 | Mgi Jnum | J:338798 |
| Mgi Id | MGI:7514698 | Doi | 10.1002/ijc.34564 |
| Citation | Kastana P, et al. (2023) Genetic deletion or tyrosine phosphatase inhibition of PTPRZ1 activates c-Met to up-regulate angiogenesis and lung adenocarcinoma growth. Int J Cancer 153(5):1051-1066 |
| abstractText | Protein tyrosine phosphatase receptor zeta 1 (PTPRZ1) is a transmembrane tyrosine phosphatase (TP) expressed in endothelial cells and required for stimulation of cell migration by vascular endothelial growth factor A(165) (VEGFA(165) ) and pleiotrophin (PTN). It is also over or under-expressed in various tumor types. In this study, we used genetically engineered Ptprz1(-/-) and Ptprz1(+/+) mice to study mechanistic aspects of PTPRZ1 involvement in angiogenesis and investigate its role in lung adenocarcinoma (LUAD) growth. Ptprz1(-/-) lung microvascular endothelial cells (LMVEC) have increased angiogenic features compared with Ptprz1(+/+) LMVEC, in line with the increased lung angiogenesis and the enhanced chemically induced LUAD growth in Ptprz1(-/-) compared with Ptprz1(+/+) mice. In LUAD cells isolated from the lungs of urethane-treated mice, PTPRZ1 TP inhibition also enhanced proliferation and migration. Expression of beta 3 (beta(3) ) integrin is decreased in Ptprz1(-/-) LMVEC, linked to enhanced VEGF receptor 2 (VEGFR2), c-Met tyrosine kinase (TK) and Akt kinase activities. However, only c-Met and Akt seem responsible for the enhanced endothelial cell activation in vitro and LUAD growth and angiogenesis in vivo in Ptprz1(-/-) mice. A selective PTPRZ1 TP inhibitor, VEGFA(165) and PTN also activate c-Met and Akt in a PTPRZ1-dependent manner in endothelial cells, and their stimulatory effects are abolished by the c-Met TK inhibitor (TKI) crizotinib. Altogether, our data suggest that low PTPRZ1 expression is linked to worse LUAD prognosis and response to c-Met TKIs and uncover for the first time the role of PTPRZ1 in mediating c-Met activation by VEGFA and PTN. |
