Assembly and activation of neurotrophic factor receptor complexes

Simi, Anastasia; Ibáñez, Carlos F.

doi:10.1002/dneu.20773

Cited by 26 publications

(23 citation statements)

References 55 publications

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“…The Trk receptor kinases play crucial roles in the development and maintenance of the central and peripheral nervous system, and consist of an extracellular ligand-binding domain, a single transmembrane domain and an intracellular tyrosine kinase domain. Upon activation, the receptor kinases initiate downstream signaling cascades mediated by Ras/Raf/MAP kinase, PI3K/Akt and PLC-γ [2-4]. TrkB and its ligand BDNF are highly expressed in biologically unfavourable neuroblastomas, and TrkB expression is associated with drug resistance and expression of angiogenic factors [5].…”

Section: Resultsmentioning

confidence: 99%

Brain-derived neurotrophic factor receptor TrkB exists as a preformed dimer in living cells

Shen

Maruyama

2012

JMS

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BackgroundNeurotrophins (NTs) and their receptors play crucial roles in the development, functions and maintenance of nervous systems. It is widely believed that NT-induced dimerization of the receptors initiates the transmembrane signaling. However, it is still controversial whether the receptor molecule has a monomeric or dimeric structure on the cell surface before its ligand binding.FindingsUsing chemical cross-linking, bimolecular fluorescence complementation (BiFC) and luciferase fragment complementation (LFC) assays, in this study, we show the brain-derived neurotrophic factor (BDNF) receptor TrkB exists as a homodimer before ligand binding. We have also found by using BiFC and LFC that the dimer forms in the endoplasmic reticulum (ER), and that the receptor lacking its intracellular domain cannot form the dimeric structure.ConclusionsMost, if not all, of the TrkB receptor has a preformed, yet inactive, homodimeric structure before BDNF binding. The intracellular domain of TrkB plays a crucial role in the spontaneous dimerization of the newly synthesized receptors, which occurs in ER. These findings provide new insight into an understanding of a molecular mechanism underlying transmembrane signaling mediated by NT receptors.

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Section: Resultsmentioning

confidence: 99%

Brain-derived neurotrophic factor receptor TrkB exists as a preformed dimer in living cells

Shen

Maruyama

2012

JMS

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“…TrkB is found throughout the central and peripheral nervous systems, and TrkC is widely expressed in mammalian neural tissues [61,72,73]. Activation of Trk initiates downstream signaling cascades mediated by Ras/Raf/MAP kinase, PI3K/Akt and PLC-γ [74,75,76]. Aberrant activation of Trk kinases is often observed in human cancers.…”

Section: Rtks and Their Ligandsmentioning

confidence: 99%

Mechanisms of Activation of Receptor Tyrosine Kinases: Monomers or Dimers

Maruyama

2014

Cells

171

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Receptor tyrosine kinases (RTKs) play essential roles in cellular processes, including metabolism, cell-cycle control, survival, proliferation, motility and differentiation. RTKs are all synthesized as single-pass transmembrane proteins and bind polypeptide ligands, mainly growth factors. It has long been thought that all RTKs, except for the insulin receptor (IR) family, are activated by ligand-induced dimerization of the receptors. An increasing number of diverse studies, however, indicate that RTKs, previously thought to exist as monomers, are present as pre-formed, yet inactive, dimers prior to ligand binding. The non-covalently associated dimeric structures are reminiscent of those of the IR family, which has a disulfide-linked dimeric structure. Furthermore, recent progress in structural studies has provided insight into the underpinnings of conformational changes during the activation of RTKs. In this review, I discuss two mutually exclusive models for the mechanisms of activation of the epidermal growth factor receptor, the neurotrophin receptor and IR families, based on these new insights.

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“…The p75 low-affinity neurotrophin receptor (p75 NTR ) is also activated by a number of trophic factors (Simi & Ibanez, 2010). p75 NTR can bind all of the neurotrophins, but when compared to the Trks, striking differences in structure and intracellular signal transduction have been discovered (Charalampopoulos et al, 2012).…”

Section: Neurotrophic Factors In Sensory Neuron Developmentmentioning

confidence: 99%

Molecular Control of the Neural Crest and Peripheral Nervous System Development

Newbern

2015

Current Topics in Developmental Biology

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A transient and unique population of multipotent stem cells, known as neural crest cells (NCCs), generate a bewildering array of cell types during vertebrate development. An attractive model among developmental biologists, the study of NCC biology has provided a wealth of knowledge regarding the cellular and molecular mechanisms important for embryogenesis. Studies in numerous species have defined how distinct phases of NCC specification, proliferation, migration, and survival contribute to the formation of multiple functionally distinct organ systems. NCC contributions to the peripheral nervous system (PNS) are well known. Critical developmental processes have been defined that provide outstanding models for understanding how extracellular stimuli, cell–cell interactions, and transcriptional networks cooperate to direct cellular diversification and PNS morphogenesis. Dissecting the complex extracellular and intracellular mechanisms that mediate the formation of the PNS from NCCs may have important therapeutic implications for neurocristopathies, neuropathies, and certain forms of cancer.

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Assembly and activation of neurotrophic factor receptor complexes

Cited by 26 publications

References 55 publications

Brain-derived neurotrophic factor receptor TrkB exists as a preformed dimer in living cells

Brain-derived neurotrophic factor receptor TrkB exists as a preformed dimer in living cells

Mechanisms of Activation of Receptor Tyrosine Kinases: Monomers or Dimers

Molecular Control of the Neural Crest and Peripheral Nervous System Development

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