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Regulation of VEGFR2 trafficking and signaling by Rab GTPase-activating proteins.

ABSTRACT: Vascular endothelial growth factor receptor-2 (VEGFR2) and its ligands (VEGFs) are crucial players in vasculogenesis and angiogenesis. General blocking of this signaling system with antibodies or small molecule inhibitors is an established strategy to treat cancer and age-related macular degeneration. Nevertheless, the activated receptor can signal to discrete downstream signaling pathways and the equilibrium between these pathways is modulated by coreceptors and distinct isoforms of VEGF. Here we investigated the influence of Rab GTPase activating proteins (RabGAPs) on VEGFR2 signaling, tube formation, and migration of endothelial cells. We demonstrate that members of the TBC1D10 subfamily of RabGAPs have opposite effects. Whereas TBC1D10A leads to increased Erk1/2 signaling, TBC1D10B lowered Erk1/2 and p38 signaling and reduced tube formation in vitro. TBC1D10A is a RabGAP acting on RAB13 that was shown before to play a role in angiogenesis and we could indeed show colocalization of these two proteins with VEGFR2 in activated cells. In addition, we observed that cells expressing TBC1D10B show lower expression of VEGFR2 and NRP1 on filopodia of activated cells. Taken together, our systematic analysis of influence of RabGAPs on VEGFR2 signaling identifies the TBC1D10 subfamily members as modulators of angiogenesis.

SUBMITTER: Xie Y

PROVIDER: S-EPMC6746989 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Regulation of VEGFR2 trafficking and signaling by Rab GTPase-activating proteins.

Xie Ye Y Mansouri Maysam M Rizk Aurélien A Berger Philipp P

Scientific reports 20190916 1

Vascular endothelial growth factor receptor-2 (VEGFR2) and its ligands (VEGFs) are crucial players in vasculogenesis and angiogenesis. General blocking of this signaling system with antibodies or small molecule inhibitors is an established strategy to treat cancer and age-related macular degeneration. Nevertheless, the activated receptor can signal to discrete downstream signaling pathways and the equilibrium between these pathways is modulated by coreceptors and distinct isoforms of VEGF. Here ...[more]

PMID: 31527750

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Project description:UnlabelledRas-associated binding (Rab) proteins and Rab-associated proteins are key regulators of vesicle transport, which is essential for the delivery of proteins to specific intracellular locations. More than 60 human Rab proteins have been identified, and their function has been shown to depend on their interaction with different Rab-associated proteins regulating Rab activation, post-translational modification and intracellular localization. The number of known inherited disorders of vesicle trafficking due to Rab cycle defects has increased substantially during the past decade. This review describes the important role played by Rab proteins in a number of rare monogenic diseases as well as common multifactorial human ones. Although the clinical phenotype in these monogenic inherited diseases is highly variable and dependent on the type of tissue in which the defective Rab or its associated protein is expressed, frequent features are hypopigmentation (Griscelli syndrome), eye defects (Choroideremia, Warburg Micro syndrome and Martsolf syndrome), disturbed immune function (Griscelli syndrome and Charcot-Marie-Tooth disease) and neurological dysfunction (X-linked non-specific mental retardation, Charcot-Marie-Tooth disease, Warburg Micro syndrome and Martsolf syndrome). There is also evidence that alterations in Rab function play an important role in the progression of multifactorial human diseases, such as infectious diseases and type 2 diabetes. Rab proteins must not only be bound to GTP, but they need also to be 'prenylated'-i.e. bound to the cell membranes by isoprenes, which are intermediaries in the synthesis of cholesterol (e.g. geranyl geranyl or farnesyl compounds). This means that isoprenylation can be influenced by drugs such as statins, which inhibit isoprenylation, or biphosphonates, which inhibit that farnesyl pyrophosphate synthase necessary for Rab GTPase activity.ConclusionAlthough protein-trafficking disorders are clinically heterogeneous and represented in almost every subspeciality of pediatrics, the identification of common pathogenic mechanisms may provide a better diagnosis and management of patients with still unknown Rab cycle defects and stimulate the development of therapeutic agents.

Dataset Information

Regulation of VEGFR2 trafficking and signaling by Rab GTPase-activating proteins.

Publications

Regulation of VEGFR2 trafficking and signaling by Rab GTPase-activating proteins.

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