Research ArticleBiochemistry

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

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Science Signaling  08 May 2018:
Vol. 11, Issue 529, eaao4006
DOI: 10.1126/scisignal.aao4006

RTKs on a new Trk

The conventional mechanism of receptor tyrosine kinase (RTK) activation is ligand-induced dimerization in the plasma membrane, upon which one monomer phosphorylates the other to initiate downstream, intracellular signaling and receptor internalization. However, using live-cell fluorescence imaging, Zahavi et al. found that the RTK TrkB in rodent neurons is internalized as a monomer. Only then in endosomes does TrkB dimerize, both independently of and (markedly more so) in response to the presence of its ligand BDNF in the endosome. The same behavior was observed when TrkB was expressed in a human cell line. These findings and future technological advances may challenge the generalized dogma of dimer-initiated RTK signaling.


Tropomyosin-related tyrosine kinase B (TrkB) is the receptor for brain-derived neurotrophic factor (BDNF) and provides critical signaling that supports the development and function of the mammalian nervous system. Like other receptor tyrosine kinases (RTKs), TrkB is thought to signal as a dimer. Using cell imaging and biochemical assays, we found that TrkB acted as a monomeric receptor at the plasma membrane regardless of its binding to BDNF and initial activation. Dimerization occurred only after the internalization and accumulation of TrkB monomers within BDNF-containing endosomes. We further showed that dynamin-mediated endocytosis of TrkB-BDNF was required for the effective activation of the kinase AKT but not of the kinase ERK1/2. Thus, we report a previously uncharacterized mode of monomeric signaling for an RTK and a specific role for the endosome in TrkB homodimerization.

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