Cell Survival through Trk Neurotrophin Receptors Is Differentially Regulated by Ubiquitination

Arévalo, Juan Carlos; Waite, Janelle; Rajagopal, Rithwick; Beyna, Mercedes; Chen, Zhe-Yu; Lee, Francis S.; Chao, Moses V.

doi:10.1016/j.neuron.2006.03.044

Cited by 174 publications

(201 citation statements)

References 49 publications

(62 reference statements)

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“…As for many other receptor tyrosine kinases, internalization of Trk proteins is promoted by ubiquitination (Geetha et al, 2005;Makkerh et al, 2005;Arevalo et al, 2006). These studies alternatively conclude that p75 NTR suppresses Trk ubiquitination (Makkerh et al, 2005) or promotes Trk ubiquitination (Geetha et al, 2005).…”

Section: The Neurotrophin Receptors: a Brief Summary Of Signaling Mecmentioning

confidence: 81%

Neurotrophin receptors: Old friends with new partners

Schecterson

Bothwell

2010

Developmental Neurobiology

112

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ABSTRACT:Neurotrophins are important regulators of embryonic development and adult function of most populations of neurons in vertebrate nervous systems. This signaling system regulates many diverse activities, including survival, axon outgrowth, and synaptic plasticity. In mammals, neurotrophin action is mediated by four receptors, p75 NTR , TrkA, TrkB, and TrkC. Although early studies viewed these receptors as solitary agents in the cells outer membrane, recent discoveries reveal that the cell outer membrane is a crowded and highly interactive neighborhood. Neurotrophin receptors partner with a diverse array of membrane proteins, dramatically expanding their functional repertoire. This review will focus on some of the most recent discoveries concerning the promiscuous partnering of neurotrophin receptors. '

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Section: The Neurotrophin Receptors: a Brief Summary Of Signaling Mecmentioning

confidence: 81%

Neurotrophin receptors: Old friends with new partners

Schecterson

Bothwell

2010

Developmental Neurobiology

112

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“…Anti-TrkB antibody was from BioVision. Anti-pTrkB 816 has been described previously (34 (21). TrkA F592A and TrkB F616A mice, and TrkB +/− , TrkC +/− , and BDNF +/− C57BL/6 mice, were bred in a pathogen-free environment in accordance with Emory Medical School guidelines.…”

Section: Methodsmentioning

confidence: 99%

N -acetylserotonin activates TrkB receptor in a circadian rhythm

Jang

Liu

Sompol

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

179

166

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Brain-derived neurotrophic factor (BDNF) is a cognate ligand for the TrkB receptor. BDNF and serotonin often function in a cooperative manner to regulate neuronal plasticity, neurogenesis, and neuronal survival. Here we show that NAS (N-acetylserotonin) swiftly activates TrkB in a circadian manner and exhibits antidepressant effect in a TrkB-dependent manner. NAS, a precursor of melatonin, is acetylated from serotonin by AANAT (arylalkylamine Nacetyltransferase). NAS rapidly activates TrkB, but not TrkA or TrkC, in a neurotrophin-and MT3 receptor-independent manner. Administration of NAS activates TrkB in BDNF knockout mice. Furthermore, NAS, but not melatonin, displays a robust antidepressant-like behavioral effect in a TrkB-dependent way. Endogenous TrkB is activated in wild-type C3H/f +/+ mice but not in AANAT-mutated C57BL/ 6J mice, in a circadian rhythm; TrkB activation is high at night in the dark and low during the day. Hence, our findings support that NAS is more than a melatonin precursor, and that it can potently activate TrkB receptor.B rain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which includes nerve growth factor, NT-3, NT-4, and NT-5 (1). BDNF binding to TrkB triggers its dimerization through conformational changes and autophosphorylation of tyrosine residues in its intracellular domain, leading to activation of the three major downstream signaling cascades including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase, and phospholipase C-γ1 (2, 3). Through these pathways, BDNF mediates a variety of neuronal activities involved in neuronal survival, neurogenesis, synaptic plasticity, and so forth, and is implicated in numerous neurological diseases. For instance, loss of BDNF plays a major role in the pathophysiology of depression, and its restoration that induces neuroplastic changes may underlie the action of antidepressant efficacy (4-7).Daily rhythms in indole metabolism are a unique characteristic of the pineal gland. Pineal serotonin (5-HT) levels are higher during the day than at night. Conversely, pineal N-acetylserotonin (NAS) and melatonin levels are low during the day and high at night (8). The switch between day and night profiles of pineal indoles is predominantly regulated by the activity of arylalkylamine N-acetyltransferase (AANAT), which escalates at night 10-to 100-fold (9). AANAT metabolizes serotonin into NAS. AANAT mRNA is prominently expressed in the pineal gland and retina, and weakly in other regions of brain (10-12). NAS is mainly synthesized in the pineal gland, and is subsequently methylated by hydroxyindole-O-methyltransferase to synthesize melatonin. Until recently, NAS was considered only as the precursor of melatonin in the process of melatonin biosynthesis from serotonin. Melatonin is highly lipophilic and is not stored at significant levels. Accordingly, it is released into the blood immediately upon synthesis. Melatonin's role in the regulation of circadian rhythms and other functions is mediated primarily by me...

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“…6A, no signal corresponding to Lys 48 chains was detected in DAT immunoprecipitates whereas a strong Lys 63 chain ubiquitination was associated with DAT that was recovered from PMA-treated cells. In control experiments, both chain-specific (Lys 63 -or Lys 48 -linked) antibodies demonstrated selective recognition of corresponding ubiquitin chain standards (Fig. 6B).…”

Section: Ube2d and Ube2l3 E2-conjugating Enzymes Are Necessary For Lysmentioning

confidence: 99%

“…In our previous mass spectrometry analysis of DAT modifications, mostly Lys 63 -linked chains and traces of Lys 48 chains were detected (13). Therefore, we examined DAT ubiquitination using recently developed antibodies that recognize two major types of ubiquitin chains, Lys 48 -or Lys 63 -linked chains, with high selectivity (42). As shown in Fig.…”

Section: Ube2d and Ube2l3 E2-conjugating Enzymes Are Necessary For Lysmentioning

confidence: 99%

“…Proteins can be mono-and polyubiquitinated. Polyubiquitin chains can be formed by conjugation of ubiquitin to any of seven lysines in the ubiquitin molecule, although chains linked through Lys 48 and Lys 63 are most commonly found. Monoubiquitination and Lys 63 polyubiqutination of transmembrane proteins are thought to represent the major sorting signals controlling their trafficking (2, 8 -12).…”

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confidence: 99%

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Lysine 63-linked Polyubiquitination of the Dopamine Transporter Requires WW3 and WW4 Domains of Nedd4-2 and UBE2D Ubiquitin-conjugating Enzymes

Viña-Vilaseca

Sorkin

2010

Journal of Biological Chemistry

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RNA interference screen previously revealed that a HECTdomain E3 ubiquitin ligase, neuronal precursor cell expressed, developmentally down-regulated 4-2 (Nedd4-2), is necessary for ubiquitination and endocytosis of the dopamine transporter (DAT) induced by the activation of protein kinase C (PKC). To further confirm the role of Nedd4-2 in DAT ubiquitination and endocytosis, we demonstrated that the depletion of Nedd4-2 by two different small interfering RNA (siRNA) duplexes suppressed PKC-dependent ubiquitination and endocytosis of DAT in human and porcine cells, whereas knock-down of a highly homologous E3 ligase, Nedd4-1, had no effect on DAT. The abolished DAT ubiquitination in Nedd4-2-depleted cells was rescued by expression of recombinant Nedd4-2. Moreover, overexpression of Nedd4-2 resulted in increased PKC-dependent ubiquitination of DAT. Mutational inactivation of the HECT domain of Nedd4-2 inhibited DAT ubiquitination and endocytosis. Structure-function analysis of Nedd4-2-mediated DAT ubiquitination revealed that the intact WW4 domain and to a lesser extent WW3 domain are necessary for PKC-dependent DAT ubiquitination. Moreover, a fragment of the Nedd4-2 molecule containing WW3, WW4, and HECT domains was sufficient for fully potentiating PKC-dependent ubiquitination of DAT. Analysis of DAT ubiquitination using polyubiquitin chain-specific antibodies showed that DAT is mainly conjugated with Lys 63 -linked ubiquitin chains. siRNA analysis demonstrated that this polyubiquitination is mediated by Nedd4-2 cooperation with UBE2D and UBE2L3 E2 ubiquitin-conjugating enzymes. The model is proposed whereby each ubiquitinated DAT molecule is modified by a single four-ubiquitin Lys 63 -linked chain that can be conjugated to various lysine residues of DAT.Post-translational modification of proteins by ubiquitination has recently emerged as an important mechanism governing membrane trafficking processes. Ubiquitin moieties attached to integral membrane proteins serve to target these proteins for rapid internalization at the cell surface and, after internalization, to lysosomes for degradation (1-3). In addition, ubiquitination of the components of internalization and endosomal sorting machineries regulate interactions and turnover of these proteins (1, 4 -5).Ubiquitination is accomplished through sequential actions of the E1 ubiquitin-activating enzyme, E2 ubiquitin-conjugating enzyme, and E3 ubiquitin ligase, the latter typically determining the substrate specificity of the reaction (6 -7). Proteins can be mono-and polyubiquitinated. Polyubiquitin chains can be formed by conjugation of ubiquitin to any of seven lysines in the ubiquitin molecule, although chains linked through Lys We have recently demonstrated that ubiquitination mediates protein kinase C (PKC) 2 -dependent endocytosis of the human dopamine transporter (DAT) (13-15). Upon PKC activation by phorbol esters, heterologously expressed DAT is internalized via a clathrin-dependent endocytic pathway and degraded in lysosomes (16,17). Ubiquitination of thre...

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Cell Survival through Trk Neurotrophin Receptors Is Differentially Regulated by Ubiquitination

Cited by 174 publications

References 49 publications

Neurotrophin receptors: Old friends with new partners

Neurotrophin receptors: Old friends with new partners

N -acetylserotonin activates TrkB receptor in a circadian rhythm

Lysine 63-linked Polyubiquitination of the Dopamine Transporter Requires WW3 and WW4 Domains of Nedd4-2 and UBE2D Ubiquitin-conjugating Enzymes

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