Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors
Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary eryth...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2019.01245/full |
| _version_ | 1828864637962027008 |
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| author | Giulia Federici Lilian Varricchio Fabrizio Martelli Mario Falchi Orietta Picconi Federica Francescangeli Paola Contavalli Gabriella Girelli Agostino Tafuri Emanuel F. Petricoin Maria Mazzarini Ann Zeuner Anna Rita Migliaccio |
| author_facet | Giulia Federici Lilian Varricchio Fabrizio Martelli Mario Falchi Orietta Picconi Federica Francescangeli Paola Contavalli Gabriella Girelli Agostino Tafuri Emanuel F. Petricoin Maria Mazzarini Ann Zeuner Anna Rita Migliaccio |
| author_sort | Giulia Federici |
| collection | DOAJ |
| description | Although stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV. |
| first_indexed | 2024-12-13T04:11:47Z |
| format | Article |
| id | doaj.art-447fe24c9cc542229a4dd63665ac3b17 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-13T04:11:47Z |
| publishDate | 2019-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-447fe24c9cc542229a4dd63665ac3b172022-12-22T00:00:03ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2019-11-01910.3389/fonc.2019.01245489290Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid ProgenitorsGiulia Federici0Lilian Varricchio1Fabrizio Martelli2Mario Falchi3Orietta Picconi4Federica Francescangeli5Paola Contavalli6Gabriella Girelli7Agostino Tafuri8Emanuel F. Petricoin9Maria Mazzarini10Ann Zeuner11Anna Rita Migliaccio12IRCCS Regina Elena National Cancer Institute, Rome, ItalyTisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United StatesNational Center for Preclinical and Clinical Research and Evaluation of Pharmaceutical Drugs, Istituto Superiore di Sanità, Rome, ItalyNational HIV/AIDS Center, Istituto Superiore di Sanità, Rome, ItalyNational HIV/AIDS Center, Istituto Superiore di Sanità, Rome, ItalyOncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, ItalyOncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, ItalyImmunohematology and Transfusion Medicine Unit, “La Sapienza” University of Rome, Rome, ItalySant'Andrea Hospital—La Sapienza, Department of Clinic and Molecular Medicine “La Sapienza” University of Rome, Rome, ItalyCenter for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, United StatesDepartment of Biomedical and Neuromotorial Sciences, Alma Mater University, Bologna, ItalyOncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy0Myeloproliferative Neoplasm Research Consortium, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United StatesAlthough stem cell factor (SCF)/cKIT interaction plays key functions in erythropoiesis, cKIT signaling in human erythroid cells is still poorly defined. To provide new insights into cKIT-mediated erythroid expansion in development and disease, we performed phosphoproteomic profiling of primary erythroid progenitors from adult blood (AB), cord blood (CB), and Polycythemia Vera (PV) at steady-state and upon SCF stimulation. While AB and CB, respectively, activated transient or sustained canonical cKIT-signaling, PV showed a non-canonical signaling including increased mTOR and ERK1 and decreased DEPTOR. Accordingly, screening of FDA-approved compounds showed increased PV sensitivity to JAK, cKIT, and MEK inhibitors. Moreover, differently from AB and CB, in PV the mature 145kDa-cKIT constitutively associated with the tetraspanin CD63 and was not endocytosed upon SCF stimulation, contributing to unrestrained cKIT signaling. These results identify a clinically exploitable variegation of cKIT signaling/metabolism that may contribute to the great erythroid output occurring during development and in PV.https://www.frontiersin.org/article/10.3389/fonc.2019.01245/fullstem cell factorcKITerythropoiesispolycythemia veraerythroid progenitors |
| spellingShingle | Giulia Federici Lilian Varricchio Fabrizio Martelli Mario Falchi Orietta Picconi Federica Francescangeli Paola Contavalli Gabriella Girelli Agostino Tafuri Emanuel F. Petricoin Maria Mazzarini Ann Zeuner Anna Rita Migliaccio Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors Frontiers in Oncology stem cell factor cKIT erythropoiesis polycythemia vera erythroid progenitors |
| title | Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors |
| title_full | Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors |
| title_fullStr | Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors |
| title_full_unstemmed | Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors |
| title_short | Phosphoproteomic Landscaping Identifies Non-canonical cKIT Signaling in Polycythemia Vera Erythroid Progenitors |
| title_sort | phosphoproteomic landscaping identifies non canonical ckit signaling in polycythemia vera erythroid progenitors |
| topic | stem cell factor cKIT erythropoiesis polycythemia vera erythroid progenitors |
| url | https://www.frontiersin.org/article/10.3389/fonc.2019.01245/full |
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