Biphasic effect of PTK7 on KDR activity in endothelial cells and angiogenesis

Area of Science:

• Molecular Biology
• Cell Biology
• Biochemistry

Background:

• Protein tyrosine kinase 7 (PTK7) is a non-catalytic receptor tyrosine kinase implicated in cancer.
• The precise role of PTK7 in carcinogenesis and its interaction with vascular endothelial growth factor (VEGF) signaling remain unclear.
• Previous studies indicated PTK7 disruption suppresses VEGF-driven angiogenesis.

Purpose of the Study:

• To elucidate the molecular mechanisms by which PTK7 modulates VEGF-induced physiological effects.
• To investigate the interaction between PTK7 and key VEGF receptors, kinase insert domain receptor (KDR) and fms-related tyrosine kinase 1 (FLT-1).

Main Methods:

• Utilized human umbilical vein endothelial cells (HUVECs) and HEK293 cells for in vitro experiments.
• Employed PTK7 knockdown and treatment with soluble PTK7 (sPTK7).
• Performed in vitro binding assays and assessed KDR phosphorylation, VEGF binding, HUVEC migration, capillary-like tube formation, and in vivo angiogenesis.

Main Results:

• Soluble PTK7 (sPTK7) and PTK7 knockdown inhibited VEGF-induced KDR phosphorylation but not FLT-1 phosphorylation.
• sPTK7 directly interacted with KDR, forming oligomers.
• sPTK7 exhibited biphasic regulation of KDR activity: enhancing VEGF binding at low concentrations and inhibiting it at high concentrations, leading to dose-dependent effects on angiogenesis.

Conclusions:

• PTK7 plays a critical role in regulating VEGF-induced KDR activity and downstream angiogenic processes.
• PTK7's function is concentration-dependent, involving KDR oligomerization at low concentrations and steric hindrance at high concentrations.
• These findings reveal a novel regulatory mechanism for angiogenesis with potential implications for cancer therapy.