@phdthesis{Gupta2021,
  author    = {Gupta, Rohini},
  title     = {Intracellular self-activation of the TrkB kinase domain causes FAK phosphorylation and disrupts actin filopodia dynamics},
  doi       = {10.25972/OPUS-23382},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233829},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {The tropomysin receptor kinase B (TrkB), the receptor for the neurotrophin brain-derived neurotrophic factor (BDNF), plays an important role in neuronal survival, neuronal differentiation, and cellular plasticity. Conventionally, TrkB activation is induced by binding of BDNF at extracellular sites and subsequent dimerization of receptor monomers. Classical Trk signaling concepts have failed to explain ligand-independent signaling of intracellular TrkB or oncogenic NTRK-fusion proteins. The intracellular activation domain of TrkB consists of a tyrosine kinase core, with three tyrosine (Y) residues at positions 701, 705 and 706, that catalyzes the phosphorylation reaction between ATPγ and tyrosine. The release of cisautoinhibition of the kinase domain activates the kinase domain and tyrosine residues outside of the catalytic domain become phosphorylated. The aim of this study was to find out how ligand-independent activation of TrkB is brought about. With the help of phosphorylation mutants of TrkB, it has been found that a high, local abundance of the receptor is sufficient to activate TrkB in a ligand-independent manner. This self-activation of TrkB was blocked when either the ATP-binding site or Y705 in the core domain was mutated. The vast majority of this self-active TrkB was found at intracellular locations and was preferentially seen in roundish cells, lacking filopodia. Live cell imaging of actin dynamics showed that self-active TrkB changed the cellular morphology by reducing actin filopodia formation. Signaling cascade analysis confirmed that self-active TrkB is a powerful activator of focal adhesion kinase (FAK). This might be the reason why self-active TrkB is able to disrupt actin filopodia formation. The signaling axis from Y705 to FAK could be mimicked by expression of the soluble, cytosolic TrkB kinase domain. However, the signaling pathway was inactive, when the TrkB kinase domain was targeted to the plasmamembrane with the help of artificial myristoylation membrane anchors. A cancer-related intracellular NTRK2-fusion protein (SQSTM1-NTRK2) also underwent constitutive kinase activation. In glioblastoma-like U87MG cells, self-active TrkB kinase reduced cell migration. These constitutive signaling pathways could be fully blocked within minutes by clinically approved, anti-tumorigenic Trk inhibitors. Moreover, this study found evidences for constitutively active, intracellular TrkB in tissue of human grade IV glioblastoma. In conclusion, the data provide an explanation and biological function for selfactive, constitutive TrkB kinase domain signaling, in the absence of a ligand.},
  language  = {en}
}
@article{AndreskaLueningschroerSendtner2020,
  author    = {Andreska, Thomas and L{\"u}ningschr{\"o}r, Patrick and Sendtner, Michael},
  title     = {Regulation of TrkB cell surface expression — a mechanism for modulation of neuronal responsiveness to brain-derived neurotrophic factor},
  series = {Cell and Tissue Research},
  volume    = {382},
  journal   = {Cell and Tissue Research},
  doi       = {10.1007/s00441-020-03224-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-235055},
  pages     = {5-14},
  year      = {2020},
  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.},
  language  = {en}
}