Artículo
Functional Specificity of the Members of the Sos Family of Ras-GEF Activators: Novel Role of Sos2 in Control of Epidermal Stem Cell Homeostasis
Autor/es | Mucientes Valdivieso, Cynthia
Lorenzo Martín, Luis Francisco Fernández Parejo, Natalia García Navas, Rósula Segrelles, Carmen Calzada, Nuria Fuentes Mateos, Rocío Paramio, Jesús M. Bustelo, Xosé R. Santos, Eugenio Calvo Baltanás, Fernando |
Departamento | Universidad de Sevilla. Departamento de Fisiología Médica y Biofísica |
Fecha de publicación | 2021-04-29 |
Fecha de depósito | 2022-12-15 |
Publicado en |
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Resumen | 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 ... 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. |
Agencias financiadoras | La Caixa HR20-00164 Fundación Ramón Areces CIVP19A5942 European Commission (EC). Fondo Europeo de Desarrollo Regional (FEDER) SAF2015-66015-R; PID2019-110758RB-I00 Instituto de Salud Carlos III CB16/12/00228; CB16/12/00352; FIS PI19/00934 Gobierno regional de Castilla y León CSI252P18; CSI145P20; CLC-2017-01; SA264P18-UIC 076; CLC-2017-01 Fundación Memoria de D. Samuel Solorzano Barruso FS/32-2020 Asociación Española Contra el Cáncer GC16173472GARC Ministerio de Ciencia e Innovación (MICIN). España RTI2018-096481-B-100 Ministerio de Universidades FPU13/02923; FPU17/03912 |
Identificador del proyecto | HR20-00164
CIVP19A5942 SAF2015-66015-R PID2019-110758RB-I00 CB16/12/00228 CB16/12/00352 FIS PI19/00934 CSI252P18 CSI145P20 CLC-2017-01 SA264P18-UIC 076 CLC-2017-01 FS/32-2020 GC16173472GARC RTI2018-096481-B-100 FPU13/02923 FPU17/03912 |
Cita | Mucientes Valdivieso, C., Lorenzo Martín, L.F., Fernández Parejo, N., García Navas, R., Segrelles, C., Calzada, N.,...,Calvo Baltanás, F. (2021). 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, 13 (9), 2152. https://doi.org/10.3390/cancers13092152. |
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