Glial cell line‐derived neurotrophic factor‐induced signaling in Schwann cells

Iwase, Tamaki; Jung, Cha-Gyun; Bae, Hyun Cheol; Zhang, M.; Soliven, Betty

doi:10.1111/j.1471-4159.2005.03290.x

Cited by 123 publications

(102 citation statements)

References 73 publications

(73 reference statements)

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“…We therefore tested the effects of Tyr 687 peptides on SHP2 activity. We found that the in vitro phosphatase activity of SHP2 recovered in immunoprecipitates from transfected COS cells was strongly enhanced by the addition of the phospho-Tyr 687 peptide but not by the corresponding non-phosphorylated peptide and could be blocked by the phosphatase inhibitor Na 3 VO 4 (Fig. 1C).…”

Section: Identification Of Shp2 As a Direct And Specific Interactor Omentioning

confidence: 86%

“…Together with the neurotrophins, glial cell line-derived neurotrophic factor (GDNF) 4 and related family members are among the most important neurotrophic factors in mammals. Because of the potent prosurvival and neuroprotective effects of GDNF on midbrain dopaminergic neurons, much of the initial interest in GDNF was focused on its possible therapeutic effects in Parkinson disease (1,2).…”

mentioning

confidence: 99%

“…In the present study, we 46-8-33-95-48; E-mail: carlos.ibanez@ki.se. 4 The abbreviations used are: GDNF, glial cell line-derived neurotrophic factor; RTK, receptor tyrosine kinase; SH2 and SH3, Src homology 2 and 3, respectively; PKA, protein kinase A; SCG, superior cervical ganglion; DIV, day in vitro. …”

mentioning

confidence: 99%

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Protein-tyrosine Phosphatase SHP2 Contributes to GDNF Neurotrophic Activity through Direct Binding to Phospho-Tyr687 in the RET Receptor Tyrosine Kinase

Perrinjaquet¹,

Vilar²,

Ibáñez

2010

Journal of Biological Chemistry

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The signaling mechanisms by which neurotrophic receptors regulate neuronal survival and axonal growth are still incompletely understood. In the receptor tyrosine kinase RET, a receptor for GDNF (glial cell line-derived neurotrophic factor), the functions of the majority of tyrosine residues that become phosphorylated are still unknown. Here we have identified the protein-tyrosine phosphatase SHP2 as a novel direct interactor of RET and the first effector known to bind to phosphorylated Tyr 687 in the juxtamembrane region of the receptor. We show that SHP2 is recruited to RET upon ligand binding in a cooperative fashion, such that both interaction with Tyr 687 and association with components of the Tyr 1062 signaling complex are required for stable recruitment of SHP2 to the receptor. SHP2 recruitment contributes to the ability of RET to activate the PI3K/AKT pathway and promote survival and neurite outgrowth in primary neurons. Furthermore, we find that activation of protein kinase A (PKA) by forskolin reduces the recruitment of SHP2 to RET and negatively affects ligand-mediated neurite outgrowth. In agreement with this, mutation of Ser 696 , a known PKA phosphorylation site in RET, enhances SHP2 binding to the receptor and eliminates the effect of forskolin on ligand-induced outgrowth. Together, these findings establish SHP2 as a novel positive regulator of the neurotrophic activities of RET and reveal Tyr 687 as a critical platform for integration of RET and PKA signals. We anticipate that several other phosphotyrosines of unknown function in neuronal receptor tyrosine kinases will also support similar regulatory functions.Neurotrophic factors regulate neuronal survival, morphology, and function and are essential for the development and maintenance of the nervous system. Together with the neurotrophins, glial cell line-derived neurotrophic factor (GDNF) 4 and related family members are among the most important neurotrophic factors in mammals. Because of the potent prosurvival and neuroprotective effects of GDNF on midbrain dopaminergic neurons, much of the initial interest in GDNF was focused on its possible therapeutic effects in Parkinson disease (1, 2). It has more recently been appreciated that GDNF and related factors affect a host of important processes in mature neurons and their precursors and also outside the nervous system. GDNF signals by binding to a receptor complex formed by the ligand-binding subunit GFR␣1 and the signaling subunit RET, a member of the receptor tyrosine kinase (RTK) family (3). GFR␣1 also associates with the neural cell adhesion molecule, NCAM, to mediate the effects of GDNF independently of RET (4 -6). Some of the activities of GDNF can also be mediated by GFR␣1 in the absence of either RET or NCAM, suggesting alternative mechanisms of transmembrane signaling (7,8). A thorough understanding of the molecular mechanisms by which GDNF functions in different contexts will be essential to elucidating its contribution to nervous system development and exploiting its therapeutic poten...

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Section: Identification Of Shp2 As a Direct And Specific Interactor Omentioning

confidence: 86%

mentioning

confidence: 99%

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Protein-tyrosine Phosphatase SHP2 Contributes to GDNF Neurotrophic Activity through Direct Binding to Phospho-Tyr687 in the RET Receptor Tyrosine Kinase

Perrinjaquet¹,

Vilar²,

Ibáñez

2010

Journal of Biological Chemistry

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“…It has been suggested that the neurotrophic effects of GDF5 on DA neurons may be mediated indirectly through the action of glial cell line-derived neurotrophic factor (GDNF) (Sullivan and O'Keeffe 2005). To test this possibility, we adopted a similar approach to Orme et al (2013) who prevented the DA neurotrophic effects of GDNF by blocking its heparan sulphate-dependent signalling (Barnett et al 2002;Iwase et al 2005; Orme et al Supplementary Fig. 3).…”

Section: Bmpr Inhibitors Prevent Bmp2-and Gdf5-induced Neurite Outgromentioning

confidence: 99%

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

et al. 2014

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Ventral midbrain (VM) dopaminergic (DA) neurons project to the dorsal striatum via the nigrostriatal pathway to regulate voluntary movements, and their loss leads to the motor dysfunction seen in Parkinson's disease (PD). Despite recent progress in the understanding of VM DA neurogenesis, the factors regulating nigrostriatal pathway development remain largely unknown. The bone morphogenetic protein (BMP) family regulates neurite growth in the developing nervous system and may contribute to nigrostriatal pathway development. Two related members of this family, BMP2 and growth differentiation factor (GDF)5, have neurotrophic effects, including promotion of neurite growth, on cultured VM DA neurons. However, the molecular mechanisms regulating their effects on DA neurons are unknown. By characterising the temporal expression profiles of endogenous BMP receptors (BMPRs) in the developing and adult rat VM and striatum, this study identified BMP2 and GDF5 as potential regulators of nigrostriatal pathway development. Furthermore, through the use of noggin, dorsomorphin and BMPR/Smad plasmids, this study demonstrated that GDF5-and BMP2-induced neurite outgrowth from cultured VM DA neurons is dependent on BMP type I receptor activation of the Smad 1/5/8 signalling pathway.

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“…We noted pCREB was upregulated in SC nuclei following both the compressive and epineurotomy forms of ETS nerve repair. CREB phosphorylation may also occur downstream from NCAM-dependent autocrine GDNF-mediated signaling in SCs thus contributing to the SC proliferation observed in the compression and epineurotomy models (Iwase, et al 2005). pCREB was not colocalized to axons, but nuclear CREB phosphorylation secondary to long-range signaling through retrograde shuttling of receptor-ligand complexes was not evaluated (Riccio, et al 1997, Watson, et al 2001).…”

Section: Discussionmentioning

confidence: 99%

Axotomy or compression is required for axonal sprouting following end-to-side neurorrhaphy

Hayashi

Pannucci

Moradzadeh³

et al. 2008

Experimental Neurology

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End-to-side (ETS) nerve repair remains an area of intense scrutiny for peripheral nerve surgeonscientists. In this technique, the transected end of an injured nerve, representing the "recipient" is sutured to the side of an uninjured "donor" nerve. Some work suggests that the recipient limb is repopulated with regenerating collateral axonal sprouts from the donor nerve that go on to form functional synapses. Significant, unresolved questions include whether the donor nerve needs to be injured to facilitate regeneration, and whether a single donor neuron is capable of projecting additional axons capable of differentially innervating disparate targets. We serially imaged living transgenic mice (n=66) expressing spectral variants of GFP in various neuronal subsets after undergoing previously described atraumatic, compressive, or epineurotomy forms of ETS repair (n=22 per group). To evaluate the source, and target innervation of these regenerating axons, nerve morphometry and retrograde labeling was further supplemented by confocal microscopy as well as Western blot analysis. Either compression or epineurotomy with inevitable axotomy were required to facilitate axonal regeneration into the recipient limb. Progressively more injurious models were associated with improved recipient nerve reinnervation (epineurotomy: 184±57.6 myelinated axons; compression: 78.9±13.8; atraumatic: 0), increased Schwann cell proliferation (epineurotomy: 72.2% increase; compression: 39% increase) and cAMP response-element binding protein expression at the expense of a net deficit in donor axon counts distal to the repair. These differences were manifest by 150 days, at which point quantitative evidence for pruning was obtained. We conclude that ETS repair relies upon injury to the donor nerve.

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Glial cell line‐derived neurotrophic factor‐induced signaling in Schwann cells

Cited by 123 publications

References 73 publications

Protein-tyrosine Phosphatase SHP2 Contributes to GDNF Neurotrophic Activity through Direct Binding to Phospho-Tyr687 in the RET Receptor Tyrosine Kinase

Protein-tyrosine Phosphatase SHP2 Contributes to GDNF Neurotrophic Activity through Direct Binding to Phospho-Tyr687 in the RET Receptor Tyrosine Kinase

Canonical BMP–Smad Signalling Promotes Neurite Growth in Rat Midbrain Dopaminergic Neurons

Axotomy or compression is required for axonal sprouting following end-to-side neurorrhaphy

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