Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis
Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse ke...
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| Format: | Article |
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MDPI AG
2021-04-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/9/2152 |
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| author | Fernando C. Baltanás Cynthia Mucientes-Valdivieso L. Francisco Lorenzo-Martín Natalia Fernández-Parejo Rósula García-Navas Carmen Segrelles Nuria Calzada Rocío Fuentes-Mateos Jesús M. Paramio Xosé R. Bustelo Eugenio Santos |
| author_facet | Fernando C. Baltanás Cynthia Mucientes-Valdivieso L. Francisco Lorenzo-Martín Natalia Fernández-Parejo Rósula García-Navas Carmen Segrelles Nuria Calzada Rocío Fuentes-Mateos Jesús M. Paramio Xosé R. Bustelo Eugenio Santos |
| author_sort | Fernando C. Baltanás |
| collection | DOAJ |
| description | Prior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis. |
| first_indexed | 2024-03-10T11:50:39Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T11:50:39Z |
| publishDate | 2021-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-eca8166de39b463ab773a60be03f76602023-11-21T17:48:14ZengMDPI AGCancers2072-66942021-04-01139215210.3390/cancers13092152Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell HomeostasisFernando C. Baltanás0Cynthia Mucientes-Valdivieso1L. Francisco Lorenzo-Martín2Natalia Fernández-Parejo3Rósula García-Navas4Carmen Segrelles5Nuria Calzada6Rocío Fuentes-Mateos7Jesús M. Paramio8Xosé R. Bustelo9Eugenio Santos10Mechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Tumor Progression Program, CIBERONC, University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Tumor Progression Program, CIBERONC, University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca-CSIC, E-37007 Salamanca, SpainMechanisms of Cancer Program, Centro de Investigación del Cáncer (CIC), Instituto de Biología Molecular y Celular del Cáncer (IBMCC), University of Salamanca-CSIC, E-37007 Salamanca, SpainPrior reports showed the critical requirement of Sos1 for epithelial carcinogenesis, but the specific functionalities of the homologous Sos1 and Sos2 GEFs in skin homeostasis and tumorigenesis remain unclear. Here, we characterize specific mechanistic roles played by Sos1 or Sos2 in primary mouse keratinocytes (a prevalent skin cell lineage) under different experimental conditions. Functional analyses of actively growing primary keratinocytes of relevant genotypes—WT, Sos1-KO, Sos2-KO, and Sos1/2-DKO—revealed a prevalent role of Sos1 regarding transcriptional regulation and control of RAS activation and mechanistic overlapping of Sos1 and Sos2 regarding cell proliferation and survival, with dominant contribution of Sos1 to the RAS-ERK axis and Sos2 to the RAS-PI3K/AKT axis. Sos1/2-DKO keratinocytes could not grow under 3D culture conditions, but single Sos1-KO and Sos2-KO keratinocytes were able to form pseudoepidermis structures that showed disorganized layer structure, reduced proliferation, and increased apoptosis in comparison with WT 3D cultures. Remarkably, analysis of the skin of both newborn and adult Sos2-KO mice uncovered a significant reduction of the population of stem cells located in hair follicles. These data confirm that Sos1 and Sos2 play specific, cell-autonomous functions in primary keratinocytes and reveal a novel, essential role of Sos2 in control of epidermal stem cell homeostasis.https://www.mdpi.com/2072-6694/13/9/2152Sos1Sos2GEFKORas signalingkeratinocytes |
| spellingShingle | Fernando C. Baltanás Cynthia Mucientes-Valdivieso L. Francisco Lorenzo-Martín Natalia Fernández-Parejo Rósula García-Navas Carmen Segrelles Nuria Calzada Rocío Fuentes-Mateos Jesús M. Paramio Xosé R. Bustelo Eugenio Santos Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis Cancers Sos1 Sos2 GEF KO Ras signaling keratinocytes |
| title | Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis |
| title_full | Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis |
| title_fullStr | Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis |
| title_full_unstemmed | Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis |
| title_short | Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis |
| title_sort | functional specificity of the members of the sos family of ras gef activators novel role of sos2 in control of epidermal stem cell homeostasis |
| topic | Sos1 Sos2 GEF KO Ras signaling keratinocytes |
| url | https://www.mdpi.com/2072-6694/13/9/2152 |
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