Identification of Gas6, a putative ligand for Sky and Axl receptor tyrosine kinases, as a novel neurotrophic factor for hippocampal neurons

2002 ◽  
Vol 68 (2) ◽  
pp. 150-160 ◽  
Author(s):  
Hiroshi Funakoshi ◽  
Tomoko Yonemasu ◽  
Toru Nakano ◽  
Kunio Matumoto ◽  
Toshikazu Nakamura
Keyword(s):  
Neurotrophic Factor ◽  
Tyrosine Kinases ◽  
Hippocampal Neurons ◽  
Receptor Tyrosine Kinases

scholarly journals TrkB deubiquitylation by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation

2020 ◽  
Vol 133 (24) ◽  
pp. jcs247841 ◽  
Author(s):  
Carlos Martín-Rodríguez ◽  
Minseok Song ◽  
Begoña Anta ◽  
Francisco J. González-Calvo ◽  
Rubén Deogracias ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Neurotrophic Factor ◽  
Tyrosine Kinases ◽  
Hippocampal Neurons ◽  
Receptor Tyrosine Kinases ◽  
Neurotrophin Receptor ◽  
C Terminus ◽  
Carboxyl Terminal

ABSTRACTUbiquitylation of receptor tyrosine kinases (RTKs) regulates both the levels and functions of these receptors. The neurotrophin receptor TrkB (also known as NTRK2), a RTK, is ubiquitylated upon activation by brain-derived neurotrophic factor (BDNF) binding. Although TrkB ubiquitylation has been demonstrated, there is a lack of knowledge regarding the precise repertoire of proteins that regulates TrkB ubiquitylation. Here, we provide mechanistic evidence indicating that ubiquitin carboxyl-terminal hydrolase 8 (USP8) modulates BDNF- and TrkB-dependent neuronal differentiation. USP8 binds to the C-terminus of TrkB using its microtubule-interacting domain (MIT). Immunopurified USP8 deubiquitylates TrkB in vitro, whereas knockdown of USP8 results in enhanced ubiquitylation of TrkB upon BDNF treatment in neurons. As a consequence of USP8 depletion, TrkB levels and its activation are reduced. Moreover, USP8 protein regulates the differentiation and correct BDNF-dependent dendritic formation of hippocampal neurons in vitro and in vivo. We conclude that USP8 positively regulates the levels and activation of TrkB, modulating BDNF-dependent neuronal differentiation.This article has an associated First Person interview with the first author of the paper.

scholarly journals Extracellular Juxtamembrane Motif Critical for TrkB Preformed Dimer and Activation

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 932 ◽  
Author(s):  
Jianying Shen ◽  
Dang Sun ◽  
Jingyu Shao ◽  
Yanbo Chen ◽  
Keliang Pang ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Neurotrophic Factor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Inhibitory Effect ◽  
Cultured Neurons ◽  
Dimer Formation ◽  
Agonistic Antibody ◽  
Conformation Changes

Receptor tyrosine kinases are believed to be activated through ligand-induced dimerization. We now demonstrate that in cultured neurons, a substantial amount of endogenous TrkB, the receptor for brain-derived neurotrophic factor (BDNF), exists as an inactive preformed dimer, and the application of BDNF activates the pre-existing dimer. Deletion of the extracellular juxtamembrane motif (EJM) of TrkB increased the amount of preformed dimer, suggesting an inhibitory role of EJM on dimer formation. Further, binding of an agonistic antibody (MM12) specific to human TrkB-EJM activated the full-length TrkB and unexpectedly also truncated TrkB lacking ECD (TrkBdelECD365), suggesting that TrkB is activated by attenuating the inhibitory effect of EJM through MM12 binding-induced conformational changes. Finally, in cells co-expressing rat and human TrkB, MM12 could only activate TrkB human-human dimer but not TrkB human-rat TrkB dimer, indicating that MM12 binding to two TrkB monomers is required for activation. Our results support a model that TrkB preforms as an inactive dimer and BDNF induces TrkB conformation changes leading to its activation.

scholarly journals Non-receptor-tyrosine Kinases Integrate Fast Glucocorticoid Signaling in Hippocampal Neurons

2013 ◽  
Vol 288 (33) ◽  
pp. 23725-23739 ◽  
Author(s):  
Silei Yang ◽  
Francesco Roselli ◽  
Alexandre V. Patchev ◽  
Shuang Yu ◽  
Osborne F. X. Almeida
Keyword(s):  
Tyrosine Kinases ◽  
Hippocampal Neurons ◽  
Receptor Tyrosine Kinases ◽  
Glucocorticoid Signaling

scholarly journals Regulation of TrkB cell surface expression—a mechanism for modulation of neuronal responsiveness to brain-derived neurotrophic factor

2020 ◽  
Vol 382 (1) ◽  
pp. 5-14 ◽  
Author(s):  
Thomas Andreska ◽  
Patrick Lüningschrör ◽  
Michael Sendtner
Keyword(s):  
Cell Surface ◽  
Neurotrophic Factor ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Surface Expression ◽  
Brain Derived Neurotrophic Factor ◽  
Fine Tuning ◽  
Cell Surface Expression ◽  
Rapid Modulation ◽  
And Function

Abstract Neurotrophin signaling via receptor tyrosine kinases is essential for the development and function of the nervous system in vertebrates. TrkB activation and signaling show substantial differences to other receptor tyrosine kinases of the Trk family that mediate the responses to nerve growth factor and neurotrophin-3. Growing evidence suggests that TrkB cell surface expression is highly regulated and determines the sensitivity of neurons to brain-derived neurotrophic factor (BDNF). This translocation of TrkB depends on co-factors and modulators of cAMP levels, N-glycosylation, and receptor transactivation. This process can occur in very short time periods and the resulting rapid modulation of target cell sensitivity to BDNF could represent a mechanism for fine-tuning of synaptic plasticity and communication in complex neuronal networks. This review focuses on those modulatory mechanisms in neurons that regulate responsiveness to BDNF via control of TrkB surface expression.

scholarly journals Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus

2003 ◽  
Vol 163 (6) ◽  
pp. 1313-1326 ◽  
Author(s):  
Mark Henkemeyer ◽  
Olga S. Itkis ◽  
Michelle Ngo ◽  
Peter W. Hickmott ◽  
Iryna M. Ethell
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Tyrosine Kinases ◽  
Hippocampal Neurons ◽  
Receptor Tyrosine Kinases ◽  
Triple Mutant ◽  
Spine Formation ◽  
Truncating Mutation ◽  
Ephb Receptor ◽  
Spine Development

Here, using a genetic approach, we dissect the roles of EphB receptor tyrosine kinases in dendritic spine development. Analysis of EphB1, EphB2, and EphB3 double and triple mutant mice lacking these receptors in different combinations indicates that all three, although to varying degrees, are involved in dendritic spine morphogenesis and synapse formation in the hippocampus. Hippocampal neurons lacking EphB expression fail to form dendritic spines in vitro and they develop abnormal spines in vivo. Defective spine formation in the mutants is associated with a drastic reduction in excitatory glutamatergic synapses and the clustering of NMDA and AMPA receptors. We show further that a kinase-defective, truncating mutation in EphB2 also results in abnormal spine development and that ephrin-B2–mediated activation of the EphB receptors accelerates dendritic spine development. These results indicate EphB receptor cell autonomous forward signaling is responsible for dendritic spine formation and synaptic maturation in hippocampal neurons.

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