Protein Associated with Myc (PAM) Is a Potent Inhibitor of Adenylyl Cyclases

Scholich, Klaus; Pierre, Sandra; Patel, Tarun B.

doi:10.1074/jbc.m107816200

Cited by 50 publications

(77 citation statements)

References 49 publications

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“…Here, downregulation of MYCBP2 in the spinal cord of adult rats increased pain-like (nociceptive) behavior in a model for acute and inflammatory pain, suggesting an enhanced neuronal signaling (3). Consistent with the finding that MYCBP2 is a potent inhibitor of adenylyl cyclases (15)(16)(17), MYCBP2-knockdown in rat spinal cords facilitated G-protein-coupled receptor (GPCR)-induced cAMP synthesis, which plays a key role in central sensitization (3,15).…”

supporting

confidence: 62%

“…1A). Exon 11 encodes 13 amino acid N-terminal of the RCC1-like domain, a highly conserved domain necessary for MYCBP2 function (6,8,17). Deletion of exon 11 leads to a shift in the open reading frame and results in the translation of 23 new amino acids after exon 11 before to reach a premature stop codon.…”

Section: Mycbp2-deficientmentioning

confidence: 99%

“…S2). As a result, the functionally important RHD1 domain (17) and all C-terminally located amino acids including the Ring-finger domain (21), which carries the ubiquitin ligase activity, were deleted.…”

Section: Mycbp2-deficientmentioning

confidence: 99%

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The Ubiquitin Ligase MYCBP2 Regulates Transient Receptor Potential Vanilloid Receptor 1 (TRPV1) Internalization through Inhibition of p38 MAPK Signaling

Holland

Coste

Zhang

et al. 2011

Journal of Biological Chemistry

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The E3 ubiquitin ligase MYCBP2 negatively regulates neuronal growth, synaptogenesis, and synaptic strength. More recently it was shown that MYCBP2 is also involved in receptor and ion channel internalization. We found that mice with a MYCBP2-deficiency in peripheral sensory neurons show prolonged thermal hyperalgesia. Loss of MYCBP2 constitutively activated p38 MAPK and increased expression of several proteins involved in receptor trafficking. Surprisingly, loss of MYCBP2 inhibited internalization of transient receptor potential vanilloid receptor 1 (TRPV1) and prevented desensitization of capsaicin-induced calcium increases. Lack of desensitization, TRPV internalization and prolonged hyperalgesia were reversed by inhibition of p38 MAPK. The effects were TRPVspecific, since neither mustard oil-induced desensitization nor behavioral responses to mechanical stimuli were affected. In summary, we show here for the first time that p38 MAPK activation can inhibit activity-induced ion channel internalization and that MYCBP2 regulates internalization of TRPV1 in peripheral sensory neurons as well as duration of thermal hyperalgesia through p38 MAPK.The E3-ubiquitin ligase MYCBP2 (Myc-binding protein 2; also known as protein associated with Myc (PAM)) 2 is an unusual large protein with a predicted size of 510 kDa. MYCBP2 orthologs have been described in mouse as Phr1, in zebrafish as Esrom, in drosophila as Highwire and in Caenorhabditis elegans as RPM-1. While MYCBP2 mRNA is found in nearly all human tissues, its expression is exceptionally high in peripheral and central neurons (1-3). MYCBP2 has been shown to act as negative regulators of synaptic growth, synaptogenesis, and neurite growth in C. elegans (4), Drosophila (5), zebrafish (6), and mice (7,8). In C. elegans and Drosophila MYCBP2-dependent growth inhibition is largely mediated by the p38 MAPK pathway (9, 10) whereas in mice the role of p38 MAPK in MYCBP2-regulated axonal growth is less clear.Whereas growth regulation of cortical axons by MYCBP2 does not involve p38 MAPK (8), MYCBP2-dependent axonal overgrowth of spinal cord motor neurons and sensory dorsal root ganglion (DRG) neurons was regulated by p38 MAPKmediated alterations in microtubule stability (11).Besides its role in the regulation of neuronal growth, also a function of MYCBP2 in neuronal transmission has been demonstrated. In C. elegans and drosophila loss-of-function mutations in the MYCBP2 orthologs decreased the number of synaptic vesicles at cholinergic and GABAergic synapses in a p38 MAPK-dependent manner (9) and reduced strength of synaptic transmission at neuromuscular junctions (5, 12, 13). More recently, it was shown that the MYCBP2 ortholog in C. elegans, RPM-1, prevents in central neurons activity-dependent internalization of AMPA receptors by inhibiting p38 MAPK signaling through ubiquitylation of MAPK kinase kinase 12 (MAPKKK12), (14). Loss of RPM-1 caused constitutive activation of p38MAPK leading to an increased internalization of the AMPA receptor ortholog GLR1.Interestingly, in ma...

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supporting

confidence: 62%

Section: Mycbp2-deficientmentioning

confidence: 99%

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The Ubiquitin Ligase MYCBP2 Regulates Transient Receptor Potential Vanilloid Receptor 1 (TRPV1) Internalization through Inhibition of p38 MAPK Signaling

Holland

Coste

Zhang

et al. 2011

Journal of Biological Chemistry

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“…This is essential for the potent and long-term inhibition of adenylate cyclase by PAM. The ability of PAM to regulate adenylate cyclase (Scholich et al, 2001), which is presumably shared by Esrom (as the RCC1 homology domain is conserved), is particularly interesting, as cAMP levels are important modulators of growth cone responses to guidance cues Song et al, 1997). …”

Section: Discussionmentioning

confidence: 99%

Formation of the retinotectal projection requires Esrom, an ortholog of PAM (protein associated with Myc)

et al. 2005

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Visual system development is dependent on correct interpretation of cues that direct growth cone migration and axon branching. Mutations in the zebrafish esrom gene disrupt bundling and targeting of retinal axons,and also cause ectopic arborization. By positional cloning, we establish that esrom encodes a very large protein orthologous to PAM (protein associated with Myc)/Highwire/RPM-1. Unlike motoneurons in Drosophila highwire mutants, retinal axons in esrom mutants do not arborize excessively, indicating that Esrom has different functions in the vertebrate visual system. We show here that Esrom has E3 ligase activity and modulates the amount of phosphorylated Tuberin, a tumor suppressor, in growth cones. These data identify a mediator of signal transduction in retinal growth cones,which is required for topographic map formation.

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“…All hiw homologs are comprised of an N-terminal guanine-nucleotide exchange factor-like domain, two PHR repeats of unknown function, and a C-terminal RING finger that is a putative E3 ubiquitin ligase domain. hiw and its homologs have been proposed to regulate a number of candidate signaling pathways (Scholich et al, 2001;McCabe et al, 2004;Murthy et al, 2004;Nakata et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

HighwireFunction at theDrosophilaNeuromuscular Junction: Spatial, Structural, and Temporal Requirements

Wu¹,

Wairkar²,

Collins³

et al. 2005

J. Neurosci.

100

170

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Highwire is a huge, evolutionarily conserved protein that is required to restrain synaptic growth and promote synaptic transmission at the Drosophila neuromuscular junction. Current models of highwire function suggest that it may act as a ubiquitin ligase to regulate synaptic development. However, it is not known in which cells highwire functions, whether its putative ligase domain is required for function, or whether highwire regulates the synapse during development or alternatively sets cell fate in the embryo. We performed a series of transgenic rescue experiments to test the spatial, structural, and temporal requirements for highwire function. We find that presynaptic activity of highwire is both necessary and sufficient to regulate both synapse morphology and physiology. The Highwire RING domain, which is postulated to function as an E3 ubiquitin ligase, is required for highwire function. In addition, highwire acts throughout larval development to regulate synaptic morphology and function. Finally, we show that the morphological and physiological phenotypes of highwire mutants have different dosage and temporal requirements for highwire, demonstrating that highwire may independently regulate the molecular pathways controlling synaptic growth and function.

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Protein Associated with Myc (PAM) Is a Potent Inhibitor of Adenylyl Cyclases

Cited by 50 publications

References 49 publications

The Ubiquitin Ligase MYCBP2 Regulates Transient Receptor Potential Vanilloid Receptor 1 (TRPV1) Internalization through Inhibition of p38 MAPK Signaling

The Ubiquitin Ligase MYCBP2 Regulates Transient Receptor Potential Vanilloid Receptor 1 (TRPV1) Internalization through Inhibition of p38 MAPK Signaling

Formation of the retinotectal projection requires Esrom, an ortholog of PAM (protein associated with Myc)

HighwireFunction at theDrosophilaNeuromuscular Junction: Spatial, Structural, and Temporal Requirements

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