Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation?
Recently published work provide the first known evidence of a malignancy-associated regulatory mechanism, functionally connecting a phospho-regulated degron domain embedded in a receptor tyrosine kinase (RTK), with its ectopic expression in cancer, conditional to a specific autocrine growth factor s...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2023.1278402/full |
| _version_ | 1797672526817525760 |
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| author | Pierluigi Scalia Pierluigi Scalia Pierluigi Scalia Stephen J. Williams Stephen J. Williams Stephen J. Williams |
| author_facet | Pierluigi Scalia Pierluigi Scalia Pierluigi Scalia Stephen J. Williams Stephen J. Williams Stephen J. Williams |
| author_sort | Pierluigi Scalia |
| collection | DOAJ |
| description | Recently published work provide the first known evidence of a malignancy-associated regulatory mechanism, functionally connecting a phospho-regulated degron domain embedded in a receptor tyrosine kinase (RTK), with its ectopic expression in cancer, conditional to a specific autocrine growth factor signal. Mechanistically, the growth factor-triggered phosphorylation inhibits the degron domain present in the regulated RTK, blocking access to a specific degradation complex. This ultimately rescues the RTK from rapid ubiquitin-proteasome-system-mediated degradation and, most importantly, causes its cellular overexpression. This mechanism, which has been here assigned the new functional name “Over-Expression by Degradation Rescue” (OEDR), provides an additional layer and potentially preferential tool for the control of RTKs expression in cancer, in addition to other mechanisms acting at the transcriptional and messenger transcript stabilization levels. We propose this newly defined phosphorylation/ubiquitination switch-dependent signal to bear wider unexploited relevance in cell biology and human pathophysiology. The recently identified mechanism underlying an OEDR-regulated RTK is discussed herein in the context of physiological endocrine circuits and cancer. |
| first_indexed | 2024-03-11T21:31:22Z |
| format | Article |
| id | doaj.art-f25a6dd6e0464beaa2f64a2d63fa6562 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-03-11T21:31:22Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-f25a6dd6e0464beaa2f64a2d63fa65622023-09-27T09:17:48ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2023-09-011310.3389/fonc.2023.12784021278402Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation?Pierluigi Scalia0Pierluigi Scalia1Pierluigi Scalia2Stephen J. Williams3Stephen J. Williams4Stephen J. Williams5Istituto Somatogene per la Oncologia Personalizzata e la Ricerca Onco-Genomica (ISOPROG)-Somatolink Expert-Patients For Patients (EPFP) Research Network, Philadelphia, PA, United StatesIstituto Somatogene per la Oncologia Personalizzata e la Ricerca Onco-Genomica (ISOPROG)-Somatolink Expert-Patients For Patients (EPFP) Research Network, Caltanissetta, ItalyDepartment of Biology, College of Science and Technology, Temple University, Philadelphia, PA, United StatesIstituto Somatogene per la Oncologia Personalizzata e la Ricerca Onco-Genomica (ISOPROG)-Somatolink Expert-Patients For Patients (EPFP) Research Network, Philadelphia, PA, United StatesIstituto Somatogene per la Oncologia Personalizzata e la Ricerca Onco-Genomica (ISOPROG)-Somatolink Expert-Patients For Patients (EPFP) Research Network, Caltanissetta, ItalyDepartment of Biology, College of Science and Technology, Temple University, Philadelphia, PA, United StatesRecently published work provide the first known evidence of a malignancy-associated regulatory mechanism, functionally connecting a phospho-regulated degron domain embedded in a receptor tyrosine kinase (RTK), with its ectopic expression in cancer, conditional to a specific autocrine growth factor signal. Mechanistically, the growth factor-triggered phosphorylation inhibits the degron domain present in the regulated RTK, blocking access to a specific degradation complex. This ultimately rescues the RTK from rapid ubiquitin-proteasome-system-mediated degradation and, most importantly, causes its cellular overexpression. This mechanism, which has been here assigned the new functional name “Over-Expression by Degradation Rescue” (OEDR), provides an additional layer and potentially preferential tool for the control of RTKs expression in cancer, in addition to other mechanisms acting at the transcriptional and messenger transcript stabilization levels. We propose this newly defined phosphorylation/ubiquitination switch-dependent signal to bear wider unexploited relevance in cell biology and human pathophysiology. The recently identified mechanism underlying an OEDR-regulated RTK is discussed herein in the context of physiological endocrine circuits and cancer.https://www.frontiersin.org/articles/10.3389/fonc.2023.1278402/fullRTKgfUbE3LUPSdegronpDegron |
| spellingShingle | Pierluigi Scalia Pierluigi Scalia Pierluigi Scalia Stephen J. Williams Stephen J. Williams Stephen J. Williams Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation? Frontiers in Oncology RTK gf UbE3L UPS degron pDegron |
| title | Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation? |
| title_full | Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation? |
| title_fullStr | Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation? |
| title_full_unstemmed | Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation? |
| title_short | Over-expression by degradation rescue of RTKs via cancer-secreted autocrine growth factors: a Phospho-degron-driven actionable layer of post-translational regulation? |
| title_sort | over expression by degradation rescue of rtks via cancer secreted autocrine growth factors a phospho degron driven actionable layer of post translational regulation |
| topic | RTK gf UbE3L UPS degron pDegron |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2023.1278402/full |
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