TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer

Mu, Yabing; Sundar, Reshma; Thakur, Noopur; Ekman, Martin; Gudey, Shyam Kumar; Yakymovych, Mariya; Hermansson, Annika; Dimitriou, Helen; Bengoechea-Alonso, Maria T.; Ericsson, Johan; Heldin, Carl‐Henrik; Landström, Maréne

doi:10.1038/ncomms1332

Cited by 170 publications

(218 citation statements)

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“…In addition, TRAF6 has been shown to be involved in TGF-b-induced intramembrane cleavage of TbRI, resulting in the release of its intracellular domain, which then is translocated to the nucleus where it drives an invasiveness program (Mu et al 2011). First, TGF-b promotes the activation of the metalloproteinase ADAM17 (also called TACE), in a TRAF6-and protein kinase C (PKC) -z-dependent manner, which results in cleavage of TbRI just outside the plasma membrane releasing the extracellular domain (Liu et al 2009a;Mu et al 2011); the remaining plasma membrane -attached part of the receptor then becomes susceptible to an additional cleavage by g-secretase in the transmembrane segment, which releases the intracellular domain (Gudey et al 2014).…”

Section: Signaling Via Smad and Non-smad Pathwaysmentioning

confidence: 99%

“…First, TGF-b promotes the activation of the metalloproteinase ADAM17 (also called TACE), in a TRAF6-and protein kinase C (PKC) -z-dependent manner, which results in cleavage of TbRI just outside the plasma membrane releasing the extracellular domain (Liu et al 2009a;Mu et al 2011); the remaining plasma membrane -attached part of the receptor then becomes susceptible to an additional cleavage by g-secretase in the transmembrane segment, which releases the intracellular domain (Gudey et al 2014). …”

Section: Signaling Via Smad and Non-smad Pathwaysmentioning

confidence: 99%

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Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

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572

498

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Transforming growth factor b (TGF-b) family members signal via heterotetrameric complexes of type I and type II dual specificity kinase receptors. The activation and stability of the receptors are controlled by posttranslational modifications, such as phosphorylation, ubiquitylation, sumoylation, and neddylation, as well as by interaction with other proteins at the cell surface and in the cytoplasm. Activation of TGF-b receptors induces signaling via formation of Smad complexes that are translocated to the nucleus where they act as transcription factors, as well as via non-Smad pathways, including the Erk1/2, JNK and p38 MAP kinase pathways, and the Src tyrosine kinase, phosphatidylinositol 3 0 -kinase, and Rho GTPases.

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Section: Signaling Via Smad and Non-smad Pathwaysmentioning

confidence: 99%

Section: Signaling Via Smad and Non-smad Pathwaysmentioning

confidence: 99%

Signaling Receptors for TGF-β Family Members

Heldin

Moustakas

2016

Cold Spring Harb Perspect Biol

Self Cite

572

498

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“…This implies that inhibition of this protease may result in disruption of DNp63a phosphorylation. Further studies will be necessary to identify this protease, however a recent study has shown that the TNF-a Converting Enzyme (TACE) is able to mediate proteolysis of ALK5 and that TACE activity is required for accumulation of ALK5 in the nucleus [53]. The specific relevance of this finding to the generation of ALK5 IKD and phosphorylation of DNp63a is unknown because in that study TACE was shown to target the ALK5 ectodomain, which is predicted to produce a fragment greater than 34 kDa.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

DeCastro¹,

Cherukuri²,

DiRenzo³

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE December 2012 REPORT TYPE Annual Summary DATES COVERED 15November2011-14November2012 TITLE AND SUBTITLE Regulation of Mammary Stem Cell Quiescence via Post-Translational 5a. CONTRACT NUMBERModification of DeltaNp63alpha. 5b. GRANT NUMBERW81XWH-11-1-0043 5c. PROGRAM ELEMENT NUMBER AUTHOR(S)Andrew. J DeCastro, B.S., Pratima Cherukuri, M.S., James DiRenzo, PhD.5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: Andrew.J.DeCastro@Dartmouth.edu 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERDartmouth College, Hanover, NH 03755 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThis document is the Annual Summary Report on the training grant awarded to Andrew DeCastro entitled Regulation of Mammary Stem Cell Quiescence via Post-translational Modification of ∆NP63α. Here, we report our findings of the effects of TGFβ (previously validated as a kinase in our kinome screen) mediated phosphorylation of ∆NP63α on stem cell behavior and mitotic activity. Task 1 aims to determine the effects of wild-type, phospho-ablative and phospho-mimetic alleles of ∆NP63α phosphorylation on stem cell behavior in vitro. Thus far, we demonstrate that stem cell enriched populations, as indicated by ALDH1 activity, contain higher concentrations of ∆NP63α mRNA. In addition, we demonstrate that the anti-clonogenic effects of TGFβ are mediated through phosphorylation of ∆NP63α, which is rescued via ectopic expression of the phospho-ablative mutant ∆NP63α-AA. Task 2 aims to identify putative ∆NP63α-kinases and determine their role in mitotic activation. Here we further characterize TGFβ-mediated phosphorylation of ∆NP63α. We demonstrate that TGFβ phosphorylation of ∆NP63α is a destabilizing event, and dependent on the proteasomal degradation pathway. We also report a non-canonical pathway in which ALK5 (TGF...

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“…TRAF6 affects the activity of a wide range of substrates, and it acts as a crucial adaptor molecule in many signalling pathways 59. A recent study found that ROS‐induced activation of TRAF6 triggers its auto‐ubiquitination, which serves as an adaptor for the recruitment of TAB 2 and binding of TAK1 with TRAF6.…”

Section: K63‐ubiquitination Plays An Important Role In Nf‐κb Activatimentioning

confidence: 99%

The role of K63‐linked polyubiquitination in cardiac hypertrophy

Ponnusamy

Xin

et al. 2018

J Cellular Molecular Medi

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Ubiquitination, also known as ubiquitylation, is a vital post‐translational modification of proteins that play a crucial role in the multiple biological processes including cell growth, proliferation and apoptosis. K63‐linked ubiquitination is one of the vital post‐translational modifications of proteins that are involved in the activation of protein kinases and protein trafficking during cell survival and proliferation. It also contributes to the development of various disorders including cancer, neurodegeneration and cardiac hypertrophy. In this review, we summarize the role of K63‐linked ubiquitination signalling in protein kinase activation and its implications in cardiac hypertrophy. We have also provided our perspectives on therapeutically targeting K63‐linked ubiquitination in downstream effector molecules of growth factor receptors for the treatment of cardiac hypertrophy.

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TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer

Cited by 170 publications

References 28 publications

Signaling Receptors for TGF-β Family Members

Signaling Receptors for TGF-β Family Members

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

The role of K63‐linked polyubiquitination in cardiac hypertrophy

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