Brain-derived Neurotrophic Factor (BDNF) Induces Polarized Signaling of Small GTPase (Rac1) Protein at the Onset of Schwann Cell Myelination through Partitioning-defective 3 (Par3) Protein

Tep, Chhavy; Kim, Mi Lyang; Opincariu, Laura I.; Limpert, Allison S.; Chan, Jonah R.; Appel, Bruce; Carter, Bruce D.; Yoon, Sung Ok

doi:10.1074/jbc.m111.312736

Cited by 39 publications

(41 citation statements)

References 27 publications

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“…Thus, our data suggest that p75NTR-dependent cell spreading is dependent on generation of the p75NTR ICD , which in turn drives NRAGE-and NEDD9-dependent activation of Rac1. Although generation of the p75NTR ICD , NRAGE signaling and Rac1 activation have all been proposed to play important roles downstream of p75NTR (Salehi et al, 2002, Harrington et al, 2002, Domeniconi et al, 2005, Kenchappa et al, 2006, Bertrand et al, 2008, Wang et al, 2008, Kenchappa et al, 2010, Ceni et al, 2010, Tep et al, 2012, Matusica et al, 2013, this is the first study that links these events in a single cascade.…”

Section: Discussionmentioning

confidence: 97%

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p75NTR-dependent Rac1 activation requires receptor cleavage and activation of an NRAGE and NEDD9 signaling cascade

Zeinieh¹,

Salehi²,

Rajkumar³

et al. 2014

Journal of Cell Science

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The p75 neurotrophin receptor (p75NTR, also known as tumor necrosis factor receptor superfamily member 16) is implicated in diverse cellular events, but fundamental aspects of its signaling mechanisms remain unclear. To address this, we have established a novel bioassay to characterize signaling cascades activated by p75NTR. We show that in COS7 cells, p75NTR expression causes a large increase in cell surface area that relies on the activation of Rac1, and we demonstrate that the p75NTR-dependent COS7 phenotype is dependent on ADAM17-and c-secretase-dependent cleavage of p75NTR and generation of the p75NTR intracellular domain (p75NTR ICD ). We show that the p75NTR adaptor protein NRAGE (also known as MAGED1) acts downstream of the p75NTR ICD in this cascade and, through a yeast two-hybrid screen, identify NEDD9, a Cas family adaptor protein, as a novel NRAGE-binding partner that mediates p75NTR-dependent Rac1 activation and cell spreading. Our results demonstrate a crucial role for p75NTR cleavage in small GTPase activation and define a novel Rac1 activation pathway involving the p75NTR ICD , NRAGE and NEDD9.

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Section: Discussionmentioning

confidence: 97%

“…p75NTR can also mediate Rac1 regulation. In some settings, this links the activated receptor to the JNK signaling cascade and promotes apoptosis (Harrington et al, 2002), and in others, p75NTR collaborates with Par3 to localize Rac1 to the axon-glial interface and thereby promote myelination (Tep et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

p75NTR-dependent Rac1 activation requires receptor cleavage and activation of an NRAGE and NEDD9 signaling cascade

Zeinieh¹,

Salehi²,

Rajkumar³

et al. 2014

Journal of Cell Science

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“…Immunohistochemistry-Brains were sectioned at 30 m in a sagittal or coronal plane using a cryostat and used for immunohistochemistry as described (4). For p-PAK staining, tissues were subjected to antigen retrieval at 50°C for 50 min in 10 mM Tris-HCl (pH 9.0).…”

Section: Methodsmentioning

confidence: 99%

“…Of the signaling pathways that p75 activates, we focused on a small GTPase, Rac1. We have previously reported that p75 activates Rac1 in neural cultures (3,4). In cultured dorsal root ganglion neurons, Rac1 mediated up-regulation of GIRK channels through increasing phosphatidylinositol 4,5-bisphosphate synthesis, which underlies the neuronal death mechanism activated by p75 cleavage (15).…”

Section: P75 Modulates Spontaneous Firing Properties Of Purkinjementioning

confidence: 97%

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p75 Regulates Purkinje Cell Firing by Modulating SK Channel Activity through Rac1

Tian

Tep

Benedick

et al. 2014

Journal of Biological Chemistry

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Background:The role of p75 in Purkinje cells of the adult cerebellum has remained obscure. Results: In the absence of p75, RacGTP levels from the cerebellum were reduced, and the mean firing frequency for all phasic firing Purkinje cells was increased. Conclusion: p75 regulates Purkinje cell firing by activating Rac1, thereby targeting SK channel function. Significance: p75 signaling contributes to normal function of Purkinje cell firing.

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Molecular signaling mechanisms of axon–glia communication in the peripheral nervous system

Grigoryan

Birchmeier

2015

BioEssays

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In this article we discuss the molecular signaling mechanisms that coordinate interactions between Schwann cells and the neurons of the peripheral nervous system. Such interactions take place perpetually during development and in adulthood, and are critical for the homeostasis of the peripheral nervous system (PNS). Neurons provide essential signals to control Schwann cell functions, whereas Schwann cells promote neuronal survival and allow efficient transduction of action potentials. Deregulation of neuron-Schwann cell interactions often results in developmental abnormalities and diseases. Recent investigations have shown that during development, neuronally provided signals, such as Neuregulin, Jagged, and Wnt interact to fine-tune the Schwann cell lineage progression. In adult, the signal exchange between neurons and Schwann cells ensures proper nerve function and regeneration. Identification of the mechanisms of neuron-Schwann cell interactions is therefore essential for our understanding of the development, function and pathology of the peripheral nervous system as a whole.

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Brain-derived Neurotrophic Factor (BDNF) Induces Polarized Signaling of Small GTPase (Rac1) Protein at the Onset of Schwann Cell Myelination through Partitioning-defective 3 (Par3) Protein

Cited by 39 publications

References 27 publications

p75NTR-dependent Rac1 activation requires receptor cleavage and activation of an NRAGE and NEDD9 signaling cascade

p75NTR-dependent Rac1 activation requires receptor cleavage and activation of an NRAGE and NEDD9 signaling cascade

p75 Regulates Purkinje Cell Firing by Modulating SK Channel Activity through Rac1

Molecular signaling mechanisms of axon–glia communication in the peripheral nervous system

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