Endothelial Function of von Hippel-Lindau Tumor Suppressor Gene: Control of Fibroblast Growth Factor Receptor Signaling

Abstract

Abstractvon Hippel-Lindau (VHL) disease results from germline and somatic mutations in the VHL tumor suppressor gene and is characterized by highly vascularized tumors. VHL mutations lead to stabilization of hypoxia-inducible factor (HIF), which up-regulates proangiogenic factors such as vascular endothelial growth factor (VEGF). This pathway is therefore believed to underlie the hypervascular phenotypes of the VHL tumors. However, recent studies have identified novel VHL functions that are independent of the HIF-VEGF pathway. In addition, a potential role of VHL in the tumor microenvironment, which carries heterozygous VHL mutations in VHL patients, has been overlooked. Here, we report a novel HIF-independent VHL function in the endothelium. VHL knockdown in primary human microvascular endothelial cells caused defective turnover of surface fibroblast growth factor (FGF) receptor, increased extracellular signal-regulated kinase signaling, and ETS1 activation, leading to increased cell motility in response to FGF and three-dimensional cord formation in vitro. HIF-A knockdown in VHL loss-of-function endothelial cells does not impede their elevated in vitro angiogenic activity. Importantly, the elevated angiogenic response to FGF is recapitulated in Vhl-heterozygous mice. Thus, partial loss of function of VHL in endothelium may be a contributing factor in tumor angiogenesis through a HIF-VEGF-independent mechanism.

Effects of Membrane Trafficking on Signaling by Receptor Tyrosine Kinases

“…Moreover, the levels of Vps4B ATPase that regulate endosomal trafficking are down-regulated on hypoxia, which leads to the accumulation of EGFR and its increased signaling (Lin et al 2012). Similarly, loss of VHL impairs internalization of fibroblast growth factor receptor 1 (FGFR1), causing its accumulation on the cell surface and enhanced signaling leading to increased cell motility on FGF stimulation (Hsu et al 2006;Champion et al 2008). …”

Complex cellular functions of the von Hippel–Lindau tumor suppressor gene: insights from model organisms

“…In VHL mutant human ccRCC cells and primary human endothelial cells knocked down with VHL -specific RNA duplex, FGFR over-accumulates on the cell surface, leading to increased FGFR, ERK and Ets1 transcription factor activation, elevated cell motility and increased angiogenic potential in vitro (Hsu et al , 2006; Champion et al , 2008). In addition, heterozygous Vhl knockout mouse shows increased angiogenic response toward bFGF in vivo (Champion et al , 2008). Importantly, this endocytic function is at least partly independent of HIF function, as Hif-α knockdown could not rescue the cell motility phenotypes in multiple cell systems.…”

“…Homozygous VHL mutant epithelial cells are shown losing epithelial characteristics (Duchi et al , 2010; Hsouna et al , 2010). These cells as well as heterozygous VHL mutant endothelial cells overexpress FGFR (short blue bar) on the surface, contributing to their increased response to the chemotactic bFGF ligand (Dammai et al , 2003; Champion et al , 2008; Hsouna et al , 2010). Mutant VHL cells overexpress HIF-α, leading to overproduction of VEGF, which in turn induces angiogenesis (van Rooijen et al , 2009, 2010) as well as metabolic switch that mimic hypoxic response (Bishop et al , 2004; Shen et al , 2005; Zehetner et al , 2008; van Rooijen et al , 2009).…”

89Zr-Bevacizumab PET Visualizes Disease Manifestations in Patients with von Hippel–Lindau Disease

“…In addition to being hypoxia-induciblefactor-dependent, VHL protein also has hypoxia-inducible-factor-independent functions such as stabilization of microtubules, regulation of apoptosis, regulation of extracellular matrix assembly, maintenance of primary cilium (23), and control of fibroblast growth factor receptor signaling (24). Loss of hypoxia-inducible-factor-independent functions probably contributes to the development of disease manifestations, including angiogenesis.…”