Structural studies of GDNF family ligands with their receptors—Insights into ligand recognition and activation of receptor tyrosine kinase RET

Wang, Xinquan

doi:10.1016/j.bbapap.2012.10.008

Cited by 64 publications

(46 citation statements)

References 67 publications

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“…Recently, NSCLCs were reported to harbor novel gene fusions involving ROS1 [6] and RET [7,8]. RET is the receptor for members of the glial cell line-derived neurotrophic factor family (GDNF) [9,10]. The RET gene is located on chromosome 10 and encodes a receptor tyrosine kinase, and the oncogenic potential of this gene product has been suggested in several tumors, especially in thyroid cancers [11].…”

Section: Introductionmentioning

confidence: 99%

KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer

et al. 2014

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BackgroundLung cancer in nonsmokers tends to be driven by a single somatic mutation or a gene fusion. KIF5B-RET fusion is an oncogene identified in non-small cell lung cancers. In this study, we verified the oncogenic activity of KIF5B-RET fusion and investigated how KIF5B-RET activates the specific signaling pathways for cellular transformation. We aimed to provide a basis for the further development of the therapy for KIF5B-RET positive lung cancer patients.MethodsRT-PCR was used to screen for KIF5B-RET fusions in Chinese lung cancer patients. To verify the oncogenic activity of KIF5B-RET kinase in lung cancer cells, we manipulated its expression genetically followed by colony formation and tumor formation assays. The mechanism by which KIF5B-RET kinase induces proliferation was investigated by western blot, coimmunoprecipitation, and administration of RET, MAPK and STAT3 inhibitors.ResultsOur study identified a KIF5B-RET fusion in Chinese NSCLC patients and demonstrated that KIF5B-RET transfected cells showed a significantly increased proliferation rate and colony-forming ability. Furthermore, we found that KIF5B-RET fusion kinase induced multilevel activation of STAT3 at both Tyr705 and Ser727, and KIF5B-RET-STAT3 signaling related inhibitors repressed the proliferation and tumorigenicity of lung cancer cells significantly.ConclusionsOur data suggest that KIF5B-RET promotes the cell growth and tumorigenicity of non-small cell lung cancers through multilevel activation of STAT3 signaling, providing possible strategies for the treatment of KIF5B-RET positive lung cancers.

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Section: Introductionmentioning

confidence: 99%

KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer

et al. 2014

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“…The RET gene encodes a transmembrane receptor tyrosine kinase. The binding of the ligands stimulates receptor dimerization, the critical step for activation of tyrosine kinase activity . The fusion partner proteins are commonly expressed in thyroid follicular cells and possess coiled‐coil domains that enable homodimerization of the fusion RET/PTC proteins (Fig.…”

Section: Oncogenic Rearrangements In Childhood Thyroid Cancer After Tmentioning

confidence: 99%

Radiation signatures in childhood thyroid cancers after the Chernobyl accident: Possible roles of radiation in carcinogenesis

et al. 2015

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After the Tokyo Electric Power Company Fukushima Daiichi nuclear power plant accident, cancer risk from low-dose radiation exposure has been deeply concerning. The linear no-threshold model is applied for the purpose of radiation protection, but it is a model based on the concept that ionizing radiation induces stochastic oncogenic alterations in the target cells. As the elucidation of the mechanism of radiation-induced carcinogenesis is indispensable to justify the concept, studies aimed at the determination of molecular changes associated with thyroid cancers among children who suffered effects from the Chernobyl nuclear accident will be overviewed. We intend to discuss whether any radiation signatures are associated with radiation-induced childhood thyroid cancers.

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“…The possibility that under our experimental conditions GM1 may directly or indirectly affect GFRα1 receptor trafficking is rather unlikely, as GM1, 1–100 μM, had no effect on the receptor protein content in tissue lysates (sum of cytosolic and membrane receptors) or lipid rafts (membrane receptors; personal observation) at the time of the maximally increased binding of endogenous GDNF to GFRα1 and Ret phosphorylation which occurred 5 min after GM1. Taking into consideration the consensus that the final GDNF signal complex conforms to a GDNF2:GFRα12:Ret2 stoichiometry (Wang ), we hypothesize that GM1 may enhance the binding of endogenous GDNF to inactive GFRα1 and/or preformed GFRα1/Ret complexes present in lipid rafts, the existence of which has been proposed (Eketjall et al . ; Cik et al .…”

Section: Discussionmentioning

confidence: 98%

“…GDNF is a member of the GDNF family of ligands (GFLs) that also includes neurturin, artemin, and persefin (Airaksinen and Saarma 2002;Wang 2013). GFLs signal via a multicomponent receptor complex that consists of the glycosylphosphatidylinositol (GPI)-anchored to lipid rafts co-receptor GDNF-family receptor a1-4 (GFRa1-4) serving as the ligand binding site, and the common transmembrane receptor tyrosine kinase Ret (Durbec et al 1996;Trupp et al 1996) serving as the signal transducer.…”

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confidence: 99%

GM1 ganglioside enhances Ret signaling in striatum

Newburn

Duchemin

Neff

et al. 2014

Journal of Neurochemistry

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It has been proposed that GM1 ganglioside promotes neuronal growth, phenotypic expression, and survival by modulating tyrosine kinase receptors for neurotrophic factors. Our studies tested the hypothesis that GM1 exerts its neurotrophic action on dopaminergic neurons, in part, by interacting with the GDNF (glia cell-derived neurotrophic factor) receptor complex, Ret tyrosine kinase and GFRa1 coreceptor. GM1 addition to striatal slices in situ increased Ret activity in a concentration-and time-dependent manner. GM1-induced Ret activation required the whole GM1 molecule and was inhibited by the kinase inhibitors PP2 and PP1. Ret activation was followed by Tyr1062 phosphorylation and PI3 kinase/Akt recruitment. The Src kinase was associated with Ret and GM1 enhanced its phosphorylation. GM1 responses required the presence of GFRa1, and there was a GM1 concentration-dependent increase in the binding of endogenous GDNF which paralleled that of Ret activation. Neutralization of the released GDNF did not influence the Ret response to GM1, and GM1 had no effect on GDNF release. Our in situ studies suggest that GM1 via GFRa1 modulates Ret activation and phosphorylation in the striatum and provide a putative mechanism for its effects on dopaminergic neurons. Indeed, chronic GM1 treatment enhanced Ret activity and phosphorylation in the striatum of the MPTPmouse and kinase activation was associated with recovery of dopamine and DOPAC deficits.

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Structural studies of GDNF family ligands with their receptors—Insights into ligand recognition and activation of receptor tyrosine kinase RET

Cited by 64 publications

References 67 publications

KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer

KIF5B-RET fusion kinase promotes cell growth by multilevel activation of STAT3 in lung cancer

Radiation signatures in childhood thyroid cancers after the Chernobyl accident: Possible roles of radiation in carcinogenesis

GM1 ganglioside enhances Ret signaling in striatum

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