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A Novel Dual Kinase Function of the RET Proto-oncogene Negatively Regulates Activating Transcription Factor 4-mediated Apoptosis
- Source :
- Journal of Biological Chemistry. 290:11749-11761
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- The RET proto-oncogene, a tyrosine kinase receptor, is widely known for its essential role in cell survival. Germ line missense mutations, which give rise to constitutively active oncogenic RET, were found to cause multiple endocrine neoplasia type 2, a dominant inherited cancer syndrome that affects neuroendocrine organs. However, the mechanisms by which RET promotes cell survival and prevents cell death remain elusive. We demonstrate that in addition to cytoplasmic localization, RET is localized in the nucleus and functions as a tyrosine-threonine dual specificity kinase. Knockdown of RET by shRNA in medullary thyroid cancer-derived cells stimulated expression of activating transcription factor 4 (ATF4), a master transcription factor for stress-induced apoptosis, through activation of its target proapoptotic genes NOXA and PUMA. RET knockdown also increased sensitivity to cisplatin-induced apoptosis. We observed that RET physically interacted with and phosphorylated ATF4 at tyrosine and threonine residues. Indeed, RET kinase activity was required to inhibit the ATF4-dependent activation of the NOXA gene because the site-specific substitution mutations that block threonine phosphorylation increased ATF4 stability and activated its targets NOXA and PUMA. Moreover, chromatin immunoprecipitation assays revealed that ATF4 occupancy increased at the NOXA promoter in TT cells treated with tyrosine kinase inhibitors or the ATF4 inducer eeyarestatin as well as in RET-depleted TT cells. Together these findings reveal RET as a novel dual kinase with nuclear localization and provide mechanisms by which RET represses the proapoptotic genes through direct interaction with and phosphorylation-dependent inactivation of ATF4 during the pathogenesis of medullary thyroid cancer.
- Subjects :
- Threonine
endocrine system
Transcription, Genetic
endocrine system diseases
Active Transport, Cell Nucleus
Apoptosis
RET proto-oncogene
Activating Transcription Factor 4
Proto-Oncogene Mas
Biochemistry
Receptor tyrosine kinase
Cell Line, Tumor
Proto-Oncogene Proteins
Humans
Phosphorylation
Kinase activity
Promoter Regions, Genetic
Protein Kinase Inhibitors
Molecular Biology
Transcription factor
Cell Nucleus
biology
Proto-Oncogene Proteins c-ret
Dual-specificity kinase
Molecular Bases of Disease
Cell Biology
Gene Expression Regulation
Proto-Oncogene Proteins c-bcl-2
Proteolysis
Cancer research
biology.protein
Cisplatin
Apoptosis Regulatory Proteins
Tyrosine kinase
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 290
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....7ac20a5f7bfda3d1f2e68ba6381951f5