Stimulated ErbB4 internalization is necessary for neuregulin signaling in neurons
Section snippets
Materials and methods
Materials. Antibodies used were: ErbB2 (sc-284), ErbB3 (sc-285), and ErbB4 (sc-283) from Santa Cruz Biotechnology (Santa Cruz, CA); phospho-Erk (Thr202/Tyr204, #9101), phospho-Akt (Ser473, #4051), and Akt (#2966) from Cell Signaling Technology (Beverly, MA); HRP-conjugated secondary antibodies (GH9596614) were from Pierce (Rockford, IL). Streptavidin agarose-beads were from Molecular Probes (Eugene, OR). EZ-Link sulfo-NHS-biotin was from Pierce. Chemicals used were: monodansylcadavenrine (MDC,
ErbB2 and ErbB4 were internalized in NRG1-stimulated neurons
To determine whether ErbB proteins undergo endocytosis in neurons, hippocampal neurons were incubated with NHS-SS-biotin at 4 °C for 1 h to label surface proteins. Un-bound NHS-SS-biotin was washed off and neurons were incubated at 37 °C to initiate internalization. Biotinylated proteins remained on cell surface was debiotinylated by cleaving the NHS-SS-biotin disulfide bond in the cleavage buffer containing glutathione. Neurons were lysed, and internalized biotinylated proteins were purified by
Discussion
For many growth factors, intracellular signaling may be terminated by ligand-induced endocytosis of the receptor tyrosine kinases and their subsequent degradation [28]. On the other hand, receptor internalization may be necessary to mediate growth factor-stimulated signaling. For example, endocytosis of activated Trk receptors is necessary for some biological functions of neurotrophins in neurons [29], [30], [31]. Internalized Trk kinases could remain tyrosine phosphorylated and active, with
Acknowledgments
This work was supported in parts by grants from NIH (L. Mei and W.C. Xiong) and MDA (L. Mei). R.S.W. was supported in part by a Korea Research Foundation Grant (MOEHRD, KRF-2004-214-H00004).
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Neuregulin1β improves both spatial and associative learning and memory in Alzheimer model of rats possibly through signaling pathways other than Erk1/2
2019, NeuropeptidesCitation Excerpt :On the other hand, in the second set of experiments, we described, NRG1β administration 7 days after Aβ significantly restored both working and reference memories in MWM and also associative memory in step through passive avoidance paradigm. NRG1β has been found to bind to ErbB receptor and activates ErbB kinase domain, and results in phosphorylation of tyrosine residues (Liu et al., 2007), which consequently serves as docking sites for phosphopeptide-binding adaptor proteins such as ERK, PI3K–Akt, FAK, Rac1, cdc42, calcineurin, STAT3, GFAP pathways and leads in activation of further target proteins involving in memory formation (Yarden and Sliwkowski, 2001). In the third set of experiments, ERK1/2 antagonists of PD98059 didn't completely affect memory restored by NRG1β.
Proteolytic processing of Neuregulin-1
2016, Brain Research BulletinCitation Excerpt :In contrast to type I NRG1 isoforms, a single cleavage C-terminal of the EGF-like domain of NRG1 type III-β1 results in retention of the membrane bound NTF (N-terminal fragment), which could activate ErbB receptors on target cells in a juxtamembrane fashion as discussed in Taveggia et al. (Taveggia et al., 2005). Since ErbB receptor internalization is likely to be necessary for NRG1 signaling (Liu et al., 2007), it seems plausible that a membrane-bound form of NRG1 is impaired in signaling. A dual cleavage at either side of the EGF-like domain of type III NRG1 liberates the growth factor to enable paracrine signaling as shown for type I NRG1 (Fleck et al., 2013).
A kinase inhibitor screen reveals protein kinase C-dependent endocytic recycling of ErbB2 in breast cancer cells
2014, Journal of Biological ChemistryEffects of neuregulin-1β on growth-associated protein 43 expression in dorsal root ganglion neurons with excitotoxicity induced by glutamate in vitro
2013, Neuroscience ResearchCitation Excerpt :Neuregulin-1β (NRG-1β) is a growth factor with potent neuroprotective capacity (Li et al., 2007). NRG-1 is a neuron-derived trophic molecule and plays an important role in neural development, synapse formation, and synaptic plasticity by activating epidermal growth factor receptor (ErbB) receptor tyrosine kinases (Liu et al., 2007; Fenster et al., 2012). Both NRG-1 and its ErbB receptors are expressed in dorsal root ganglion (DRG) of embryonic rat and postnatal rat (Reinhard et al., 2009; Kanzaki et al., 2012).