The receptor tyrosine kinase TrkB signals without dimerization at the plasma membrane

Zahavi, Eitan Erez; Steinberg, Nili; Altman, Topaz; Chein, Michael; Joshi, Yuvraj; Gradus-Pery, Tal; Perlson, Eran

doi:10.1126/scisignal.aao4006

Cited by 30 publications

(26 citation statements)

References 43 publications

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“…Our model contrasts with the model of TrkB activation recently proposed (46). In that model TrkB is activated by its ligand BDNF and signal in a monomeric state and only after internalization in the endosomes forms dimers (46). Interestingly, and in favor of our model, using the same methodology the authors found that TrkA form dimers with NGF at the plasma membrane.…”

Section: Discussioncontrasting

confidence: 84%

Structural Basis of the Transmembrane Domain Dimerization in the Activation Mechanism of TrkA by NGF

Franco

Nadezhdin

Mineev

et al. 2019

Preprint

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Trk receptors are essential for the nervous system development. The molecular mechanism of TrkA activation by its ligand NGF is still unsolved. Recent data indicates that at endogenous levels most of TrkA is in an equilibrium monomer-dimer and the binding of NGF induces an increase of the dimer and oligomer forms of the receptor. An unsolved issue is the role of the transmembrane domain (TMD) in the dimerization of TrkA and the structural details of the TMD in the active dimer receptor. We found that TrkA-TMD can form dimers, identified the structural determinants of the dimer interface in the active receptor and validated this interface using site-directed mutagenesis together with functional and cell differentiation studies. Using in vivo crosslinking we identified a reordering of the extracellular juxtamembrane (JTM) region after ligand binding.Replacement of some residues in the JTM region with cysteine form ligand-independent active dimers and reveal a preferred dimer interface. In addition to that, insertion of leucine residues into the TMD helix induces a ligand-independent TrkA activation suggesting that a rotation of the TMD dimers could be behind TrkA activation by NGF. Altogether our data indicates that the transmembrane and juxtamembrane regions of the receptor play a key role in the dimerization and activation of TrkA by NGF.

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Section: Discussioncontrasting

confidence: 84%

Structural Basis of the Transmembrane Domain Dimerization in the Activation Mechanism of TrkA by NGF

Franco

Nadezhdin

Mineev

et al. 2019

Preprint

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“…In neurons in particular, endosomes take on an additional signaling role. Their rapid retrograde transport serves as an efficient mechanism for signal transduction across large distances (i.e., neurotrophin transport from the distal synapse to the cell body; Howe and Mobley, 2004 ), or a mechanism to regulate the nature and intensity of a signal (Zahavi et al, 2018 ). A link between endosomal trafficking and RNA silencing was first established when the RISC components Ago2 and GW182 were found to be enriched in their fraction of multivesicular bodies (MVBs), suggesting that these foci are distinct from P-bodies (Gibbings et al, 2009 ; Siomi and Siomi, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Localization of RNAi Machinery to Axonal Branch Points and Growth Cones Is Facilitated by Mitochondria and Is Disrupted in ALS

Gershoni-Emek

Altman

Ionescu

et al. 2018

Front. Mol. Neurosci.

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Local protein synthesis in neuronal axons plays an important role in essential spatiotemporal signaling processes; however, the molecular basis for the post-transcriptional regulation controlling this process in axons is still not fully understood. Here we studied the axonal mechanisms underlying the transport and localization of microRNA (miRNA) and the RNAi machinery along the axon. We first identified miRNAs, Dicer, and Argonaute-2 (Ago2) in motor neuron (MN) axons. We then studied the localization of RNAi machinery and demonstrated that mitochondria associate with miR-124 and RNAi proteins in axons. Importantly, this co-localization occurs primarily at axonal branch points and growth cones. Moreover, using live cell imaging of a functional Cy3-tagged miR-124, we revealed that this miRNA is actively transported with acidic compartments in axons, and associates with stalled mitochondria at growth cones and axonal branch points. Finally, we observed enhanced retrograde transport of miR-124-Cy3, and a reduction in its localization to static mitochondria in MNs expressing the ALS causative gene hSOD1G93A. Taken together, our data suggest that mitochondria participate in the axonal localization and transport of RNAi machinery, and further imply that alterations in this mechanism may be associated with neurodegeneration in ALS.

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“…TrkB agonists can differentially activate selective downstream pathways, and TrkB-PLCγ1 activation is complex. This concept is already evident in recent literature that has shown evidence of TrkB receptor activation and signaling without dimerization, suggesting that TrkB can under certain conditions exist and function as a monomeric receptor at the plasma membrane ( 75 ). Moreover, recent studies examining plasma membrane diffusion kinetics have demonstrated that up to 20% of the Trk family may exist as dimers or oligomers prior to neurotrophin binding ( 76 ), though their function remains a topic of debate ( 77 ).…”

Section: Discussionmentioning

confidence: 76%

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

Kipnis

Sullivan

Carter

et al. 2019

Preprint

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34Refractory neonatal seizures do not respond to first-line anti-seizure medications (ASMs) 35 like phenobarbital (PB), a positive allosteric modulator for GABAA receptors, the most widely 36 used ASM to treat neonatal seizures. GABAA receptor-mediated inhibition is dependent upon 37 neuronal chloride regulation. The electroneutral cation-chloride transporter KCC2 mediates 38 neuronal chloride extrusion; an age-dependent increase of KCC2 expression enables the shift of 39 GABAergic signaling from depolarizing to hyperpolarizing. BDNF-TrkB activation following 40 excitotoxic injury recruits downstream targets like PLCγ1, leading to KCC2 hypofunction. This 41 study investigated the efficacy of partial and full TrkB agonists; LM22A-4 (LM), HIOC and 42 Deoxygedunin (DG) respectively, on PB-refractory seizures, post-ischemic TrkB-pathway 43 activation, and KCC2 membrane stability in a P7 CD-1 mouse model of refractory neonatal 44 seizures. Anti-seizure efficacy was determined by quantifying seizure burdens with continuous 45 video-EEG. LM rescued PB-refractory seizures in a sexually dimorphic manner. LM anti-seizure 46 efficacy was associated with a significant reduction in the post-ischemic phosphorylation of 47 TrkB at Y816, a site known to mediate post-ischemic KCC2 hypofunction via PLCγ1 activation. 48 LM additionally rescued ischemia-induced pKCC2-S940 dephosphorylation preserving its 49 membrane stability. HIOC and DG, two novel full TrkB agonists, also rescued PB-refractoriness 50 and post-ischemic TrkB-PLCγ1 pathway activation. Additionally, chemogenetic inactivation of 51 TrkB significantly reduced post-ischemic neonatal seizure burdens at P7. Developmental 52 expression profiles of TrkB and KCC2 in naïve pups identified developmental differences that 53 may underlie the sex-dependent variance in anti-seizure efficacy. These results support a novel 54 role for the TrkB receptor in the emergence of age-dependent refractory neonatal seizures. 55 56 65 (KCC2) in a mouse model of acute neonatal ischemia associated with phenobarbital (PB)-66 refractory seizures (5). 67The electroneutral cation-chloride transporter KCC2 is the primary neuronal Clextruder 68 and enables hyperpolarizing GABAergic inhibition in the brain. The residue Ser940 (S940) on 69 the C-terminus of KCC2 is associated with its membrane stability and chloride extrusion 70 capacity (6, 7). The developmental switch in GABAergic signaling from depolarizing to 71 hyperpolarizing (8) is enabled by an age-dependent increase of KCC2 expression (9). In the 72 neonatal period, KCC2 expression is low and GABA is depolarizing (8-10). In addition, KCC2 73 is susceptible to degradation following excitotoxic injury (2, 11, 12). In our characterized CD-1 74 mouse model of ischemic neonatal seizures, KCC2 underwent degradation and 75 dephosphorylation of residue S940 (5). This rendered the ASM PB inefficacious (5), as PB is a 76 positive allosteric modulator of GABAA receptors (13). Prevention of BDNF-TrkB mediated 77 KCC2 hypofunction rescued PB-refractori...

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The receptor tyrosine kinase TrkB signals without dimerization at the plasma membrane

Cited by 30 publications

References 43 publications

Structural Basis of the Transmembrane Domain Dimerization in the Activation Mechanism of TrkA by NGF

Structural Basis of the Transmembrane Domain Dimerization in the Activation Mechanism of TrkA by NGF

Localization of RNAi Machinery to Axonal Branch Points and Growth Cones Is Facilitated by Mitochondria and Is Disrupted in ALS

TrkB agonists prevent post-ischemic BDNF-TrkB mediated emergence of refractory neonatal seizures in CD-1 pups

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