2026-06-14T10:38:27Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/74412025-06-13T09:04:58Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19617
Repisalud
author
Zarich-Dimitrievich, Natasha
author
Anta, Begoña
author
Fernández-Medarde, Alberto
author
Ballester, Alicia
author
de Lucas, Maria Pilar
author
Camara, Ana Belen
author
Anta-Felez, Berta
author
Oliva-Martinez, Jose Luis
author
Rojas-Cabañeros, Jose Maria
author
Santos, Eugenio
funder
Junta de Castilla y León (España)
funder
Fundación Memoria de Don Samuel Solórzano
funder
Instituto de Salud Carlos III
funder
Asociación Española Contra el Cáncer
funder
Ministerio de Economía y Competitividad (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
2019-04-09T11:35:40Z
2019-04-09T11:35:40Z
2019-01-04
Oncogenesis. 2019 Jan 4;8(1):2.
10.1038/s41389-018-0111-1
2157-9024
Oncogenesis
30631038
http://hdl.handle.net/20.500.12105/7441
Sos1 is an universal, widely expressed Ras guanine nucleotide-exchange factor (RasGEF) in eukaryotic cells. Its N-terminal HD motif is known to be involved in allosteric regulation of Sos1 GEF activity through intramolecular interaction with the neighboring PH domain. Here, we searched for other cellular proteins also able to interact productively with the Sos1 HD domain. Using a yeast two-hybrid system, we identified the interaction between the Sos1 HD region and CSN3, the third component of the COP9 signalosome, a conserved, multi-subunit protein complex that functions in the ubiquitin-proteasome pathway to control degradation of many cellular proteins. The interaction of CSN3 with the HD of Sos1 was confirmed in vitro by GST pull-down assays using truncated mutants and reproduced in vivo by co-immunoprecipitation with the endogenous, full-length cellular Sos1 protein. In vitro kinase assays showed that PKD, a COP9 signalosome-associated-kinase, is able to phosphorylate Sos1. The intracellular levels of Sos1 protein were clearly diminished following CSN3 or PKD knockdown. A sizable fraction of the endogenous Sos1 protein was found ubiquitinated in different mammalian cell types. A significant reduction of RasGTP formation upon growth factor stimulation was also observed in CSN3-silenced as compared with control cells. Our data suggest that the interaction of Sos1 with the COP9 signalosome and PKD plays a significant role in maintenance of cellular Sos1 protein stability and homeostasis under physiological conditions and raises the possibility of considering the CSN/PKD complex as a potential target for design of novel therapeutic drugs.
eng
The CSN3 subunit of the COP9 signalosome interacts with the HD region of Sos1 regulating stability of this GEF protein
research article
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https://repisalud.isciii.es/bitstreams/2bec2052-6231-428d-83b9-fc7b7f6a8541/download
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application/pdf
TheCSN3SubunitOf_2019.pdf
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https://repisalud.isciii.es/bitstreams/b96a5d27-689e-4db4-93bf-27f71aaa2e63/download
File
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6b7df4a9f65937e600a215f5b7bc5c27
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text/plain
TheCSN3SubunitOf_2019.pdf.txt