Sphingosine-1-phosphate induced mTOR-activation is mediated by the E3-ubiquitin ligase PAM

Maeurer, Christian; Holland, Sabrina M.; Pierre, Sandra; Potstada, Wiebke; Scholich, Klaus

doi:10.1016/j.cellsig.2008.10.016

Cited by 44 publications

(44 citation statements)

References 45 publications

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“…We postulate that a post-translational mechanism may be responsible for the discrepancy between the mRNA and protein levels. In certain DTC cases, DEPTOR protein is cytoplasmically enriched by re-synthesis and reduced degradation, indicating that the ubiquitin-mediated protein system may act as an upstream regulator of DEPTOR (24)(25)(26). By comparison of the cytoplasmic H-scored staining in 114 DTC cases, we observed a significantly higher H-score of DEPTOR in recurrent cases, thus indicating its influence on the recurrence of DTC.…”

Section: Discussionmentioning

confidence: 73%

Overexpression of DEP domain containing mTOR-interacting protein correlates with poor prognosis in differentiated thyroid carcinoma

et al. 2011

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Abstract. DEP domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR), a recently identified mTOR-interacting protein, is a novel candidate oncogene. Previous studies reveal that high DEPTOR expression is required to maintain PI3K and Akt activation and to inhibit apoptosis. However, its significance in differentiated thyroid carcinoma (DTC) is not yet known. The present study verifies the mRNA and protein expression of DEPTOR in five cell lines, DTC tissues and normal adjacent tissues. Tissue microarrays of 114 DTC patients were used to detect DEPTOR protein expression. The assessment of DEPTOR levels demonstrated that DEPTOR in DTC cells and tissues was significantly increased compared with normal cells and adjacent normal tissues. DEPTOR protein expression was significantly associated with lymph node status, extrathyroid extension and distant metastasis. Patients exhibiting high DEPTOR expression were statistically susceptible to earlier recurrence and poorer survival than those with low expression. Univariate and multivariate analyses showed that DEPTOR expression was an independent prognostic factor for DTC recurrence. In conclusion, our data indicate DEPTOR as a novel prognostic marker for DTC. IntroductionDifferentiated thyroid carcinoma (DTC) is the most common histological type of thyroid malignancy and its incidence is increasing (1). Although the majority of DTCs have a relative low mortality, with 10-year survival rates of 83-95%, approximately 30% of patients with DTC still undergo recurrence during the decades following initial therapy during several decades (2,3). Establishing relevant biomarkers with prognostic significance may prove crucial in reducing the recurrence rate and modifying therapeutic strategies for individual DTC patients (4). To date, few molecular prognostic indicators have been used to evaluate the efficiency of DTC patient diagnosis and prognosis (5,6).DEP domain containing mammalian target of rapamycin (mTOR)-interacting protein (DEPTOR), a recently identified 48 kDa mTOR-interacting protein, is a novel candidate oncogene (7). DEPTOR is capable of inhibiting mTORC1 signaling and activation of mTORC2 signaling (8-10). As the downstream signal of DEPTOR, mTORC2 protein complex displays PDK-2 activity leading to serine 473 phosphorylation and overactivation of the PI3K/Akt pathway (11,12). Many key functions of PI3K/Akt signaling, such as genetic mutations of kinases and regulatory proteins, epigenetic alterations and post-translational modifications, have already been confirmed by in vitro studies and clinical data in thyroid cancer and a wide variety of other tumors (13-15). The significant role of DEPTOR in regulating tumor growth and progression indicates that it may closely correlate with aggressive clinical behaviors of DTC.However, the expression level of DEPTOR in DTC is largely unknown and the role of DEPTOR in clinical progression remains to be established. Therefore, we evaluated DEPTOR expression on the mRNA and protein level in thyroid ca...

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Section: Discussionmentioning

confidence: 73%

Overexpression of DEP domain containing mTOR-interacting protein correlates with poor prognosis in differentiated thyroid carcinoma

et al. 2011

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“…One group comprised proteins representing different signaling pathways. The second group included proteins involved in transcriptional regulation, which was not unexpected, because the involvement of MYCBP2 in the regulation of transcriptional and translational regulation through Myc and mTOR signaling pathways has been demonstrated previously by different groups (1,21,41). The largest group comprised cytoskeletal associated proteins involved in growth regulation and receptor or vesicle trafficking, such as ROCK2, myosin Va, and myosin VI (31,33,42).…”

Section: Discussionmentioning

confidence: 74%

“…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. As a result a deletion of the whole RHD1 domain and all C-terminally located amino acids is reached (8,21). The construct was electroporated into ES cells and homologous recombinants containing both loxP sites were confirmed by Southern blot.…”

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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“…The identity and existence of a GEF for Rheb have not been resolved. Translationally controlled tumor protein (TCTP) (27), protein associated with Myc (PAM) (28), and soluble ␣␤-tubulin (29) have been proposed as Rheb GEFs; however, such a role for TCTP has been disputed (30,31). B, hydrolysis of GTP by wild-type Rheb and G63A in the presence and absence of the TSC2 GAP domain, monitored by real-time NMR.…”

Section: Rheb-wt-gtpmentioning

confidence: 99%

Structure-guided Mutation of the Conserved G3-box Glycine in Rheb Generates a Constitutively Activated Regulator of Mammalian Target of Rapamycin (mTOR)

Mazhab-Jafari

Marshall

et al. 2014

Journal of Biological Chemistry

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Background: GTPases regulate cellular signaling by cycling between GDP-(inactive) and GTP-(active) bound states. Results: Rheb GTPase cycling was manipulated by structure-guided mutagenesis of an ultraconserved residue. Conclusion: Constitutively activated or inactive Rheb mutants were generated by substitutions that displace the hydrolytic water or ␥-phosphate, respectively. Significance: These mutants offer new research tools, and the approach may be extended to other GTPases.

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Sphingosine-1-phosphate induced mTOR-activation is mediated by the E3-ubiquitin ligase PAM

Cited by 44 publications

References 45 publications

Overexpression of DEP domain containing mTOR-interacting protein correlates with poor prognosis in differentiated thyroid carcinoma

Overexpression of DEP domain containing mTOR-interacting protein correlates with poor prognosis in differentiated thyroid carcinoma

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

Structure-guided Mutation of the Conserved G3-box Glycine in Rheb Generates a Constitutively Activated Regulator of Mammalian Target of Rapamycin (mTOR)

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