Receptor Tyrosine Kinases Endocytosis in Endothelium

Zhang, Xi; Simons, Michael

doi:10.1161/atvbaha.114.303217

Cited by 33 publications

(17 citation statements)

References 76 publications

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“…Interestingly, we did not see a significant change in FGFR1 protein expression, but did see a trend for reduced expression following extinction. FGFR1 is part of the tyrosine kinase receptor family (Johnson and Williams, 1993) and when bound by bFGF is trafficked to the nucleus (Myers et al, 2003;Zhang and Simons, 2014). Therefore, examining synaptic or nuclear expression instead of whole-cell expression may reveal a change in FGFR1 protein localization.…”

Section: Discussionmentioning

confidence: 99%

Blocking Infralimbic Basic Fibroblast Growth Factor (bFGF or FGF2) Facilitates Extinction of Drug Seeking After Cocaine Self-Administration

Hafenbreidel

Twining

Todd

et al. 2015

Neuropsychopharmacol

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Drug exposure results in structural and functional changes in brain regions that regulate reward and these changes may underlie the persistence of compulsive drug seeking and relapse. Neurotrophic factors, such as basic fibroblast growth factor (bFGF or FGF2), are necessary for neuronal survival, growth, and differentiation, and may contribute to these drug-induced changes. Following cocaine exposure, bFGF is increased in addiction-related brain regions, including the infralimbic medial prefrontal cortex (IL-mPFC). The IL-mPFC is necessary for extinction, but whether drug-induced overexpression of bFGF in this region affects extinction of drug seeking is unknown. Thus, we determined whether blocking bFGF in IL-mPFC would facilitate extinction following cocaine self-administration. Rats were trained to lever press for intravenous infusions of cocaine before extinction. Blocking bFGF in IL-mPFC before four extinction sessions resulted in facilitated extinction. In contrast, blocking bFGF alone was not sufficient to facilitate extinction, as blocking bFGF and returning rats to their home cage had no effect on subsequent extinction. Furthermore, bFGF protein expression increased in IL-mPFC following cocaine self-administration, an effect reversed by extinction. These results suggest that cocaine-induced overexpression of bFGF inhibits extinction, as blocking bFGF during extinction permits rapid extinction. Therefore, targeted reductions in bFGF during therapeutic interventions could enhance treatment outcomes for addiction.

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Section: Discussionmentioning

confidence: 99%

Blocking Infralimbic Basic Fibroblast Growth Factor (bFGF or FGF2) Facilitates Extinction of Drug Seeking After Cocaine Self-Administration

Hafenbreidel

Twining

Todd

et al. 2015

Neuropsychopharmacol

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“…Specifically, it has been shown that NRP1 acts as a coreceptor for VEGFR2. When VEGFR2 binds NRP1, it is recycled to the plasma membrane rather than trafficked to the lysosome for degradation (8,9,28). In light of these established findings, we hypothesized that ARF6 might affect VEGFR2 trafficking by influencing its interaction with NRP1.…”

Section: Gep100-arf6 Promotes Binding Of Vegfr2 With Its Coreceptor Nmentioning

confidence: 98%

Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy

Zhu

Shi

Winter

et al. 2017

Journal of Clinical Investigation

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“…New blood vessels are generated from the preexisting ones by a series of successive steps, including endothelial sprouting and tube formation. Typically, these processes are regulated by angiogenic factors, such as vascular endothelial growth factors, 1–3 fibroblast growth factors, 4, 5 and platelet derived growth factors. 6 In particular, VEGF-A induces tip cell formation leading to vascular ingrowth into avascular areas.…”

Section: Introductionmentioning

confidence: 99%

SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling

Zhu

Ding

Qiu

et al. 2017

Circulation Research

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Rationale The highly conserved NOTCH signaling pathway functions as a key cell-cell interaction mechanism controlling cell-fate and tissue patterning, while its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls it signal transduction. Our previous study indicated the potential role of post-translational small ubiquitin-like modifier (SUMO) modification (SUMOylation) in vascular disorders. Objective To investigate the role of SUMOylation in endothelial NOTCH signaling and angiogenesis. Methods and Results Endothelial SENP1 deletion, in newly generated endothelial SENP1 (the major protease of the SUMO system) deficient mice, significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling, as confirmed in cultured endothelial cells. An in vitro SUMOylation assay and immunoprecipitation revealed that when SENP1 associated with NOTCH1 intracellular domain (N1ICD) it functions as a deSUMOylase of N1ICD SUMOylation on conserved lysines. Immunoblot and immunoprecipitation analyses and dual luciferase assays of natural and SUMO-conjugated/nonconjugated NOTCH1 forms demonstrated that SUMO conjugation facilitated NOTCH1 cleavage. This released N1ICD from the membrane and stabilized it for translocation to the nucleus where it functions as a co-transcriptional factor. Functionally, SENP1-mediated NOTCH1 deSUMOylation was required for NOTCH signal activation in response to DLL4 stimulation. This in turn suppressed VEGF receptor signaling and angiogenesis, as evidenced by immunoblotted signaling molecules and in vitro angiogenesis assays. Conclusions These results establish reversible NOTCH1 SUMOylation as a regulatory mechanism in coordinating endothelial angiogenic signaling; SENP1 acts as a critical intrinsic mediator of this process. These findings may apply to NOTCH-regulated biological events in non-vascular tissues and provide a novel therapeutic strategy for vascular diseases and tumors.

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Receptor Tyrosine Kinases Endocytosis in Endothelium

Cited by 33 publications

References 76 publications

Blocking Infralimbic Basic Fibroblast Growth Factor (bFGF or FGF2) Facilitates Extinction of Drug Seeking After Cocaine Self-Administration

Blocking Infralimbic Basic Fibroblast Growth Factor (bFGF or FGF2) Facilitates Extinction of Drug Seeking After Cocaine Self-Administration

Small GTPase ARF6 controls VEGFR2 trafficking and signaling in diabetic retinopathy

SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling

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