Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family
- Autores
- Llavero, Francisco; Montoro, Miriam Luque; Sastre, Alazne Arrazola; Fernández Moreno, David; Lacerda, Hadriano M.; Parada, Luis Antonio; Lucia, Alejandro; Zugaza, José L.
- Año de publicación
- 2019
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- We recently uncovered a regulatory pathway of the muscle isoform of glycogen phosphorylase (PYGM) that plays an important role in regulating immune function in T cells. Here, using various enzymatic, pulldown, and immunoprecipitation assays, we describe signaling cross-talk between the small GTPases RAS and RAP1A, member of RAS oncogene family (RAP1) in human Kit 225 lymphoid cells, which, in turn, is regulated by the epidermal growth factor receptor (EGFR). We found that this communication bridge is essential for glycogen phosphorylase (PYG) activation through the canonical pathway because this enzyme is inactive in the absence of adenylyl cyclase type 6 (ADCY6). PYG activation required stimulation of both exchange protein directly activated by cAMP 2 (EPAC2) and RAP1 via RAS and ADCY6 phosphorylation, with the latter being mediated by Raf-1 proto-oncogene, Ser/ Thr kinase (RAF1). Consistent with this model, PYG activation was EGFR-dependent and may be initiated by the constitutively active form of RAS. Consequently, PYG activation in Kit 225 T cells could be blocked with specific inhibitors of RAS, EPAC, RAP1, RAF1, ADCY6, and cAMP-dependent protein kinase. Our results establish a new paradigm for the mechanism of PYG activation, which depends on the type of receptor involved.
Fil: Llavero, Francisco. Universidad del País Vasco; España
Fil: Montoro, Miriam Luque. Universidad del País Vasco; España
Fil: Sastre, Alazne Arrazola. Universidad del País Vasco; España
Fil: Fernández Moreno, David. Universidad Europea de Madrid; España. Hospital 12 de Octubre; España
Fil: Lacerda, Hadriano M.. Universidad del País Vasco; España
Fil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina
Fil: Lucia, Alejandro. universidad europea de Madrid; España. Hospital 12 de Octubre; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Zugaza, José L.. Universidad del País Vasco; España. The Basque Foundation For Science; España - Materia
-
Epidermal growth factor receptor (EGFR)
RAS protein
Raf kinase
Cell signaling - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/120534
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network_name_str |
CONICET Digital (CONICET) |
spelling |
Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS familyLlavero, FranciscoMontoro, Miriam LuqueSastre, Alazne ArrazolaFernández Moreno, DavidLacerda, Hadriano M.Parada, Luis AntonioLucia, AlejandroZugaza, José L.Epidermal growth factor receptor (EGFR)RAS proteinRaf kinaseCell signalinghttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1We recently uncovered a regulatory pathway of the muscle isoform of glycogen phosphorylase (PYGM) that plays an important role in regulating immune function in T cells. Here, using various enzymatic, pulldown, and immunoprecipitation assays, we describe signaling cross-talk between the small GTPases RAS and RAP1A, member of RAS oncogene family (RAP1) in human Kit 225 lymphoid cells, which, in turn, is regulated by the epidermal growth factor receptor (EGFR). We found that this communication bridge is essential for glycogen phosphorylase (PYG) activation through the canonical pathway because this enzyme is inactive in the absence of adenylyl cyclase type 6 (ADCY6). PYG activation required stimulation of both exchange protein directly activated by cAMP 2 (EPAC2) and RAP1 via RAS and ADCY6 phosphorylation, with the latter being mediated by Raf-1 proto-oncogene, Ser/ Thr kinase (RAF1). Consistent with this model, PYG activation was EGFR-dependent and may be initiated by the constitutively active form of RAS. Consequently, PYG activation in Kit 225 T cells could be blocked with specific inhibitors of RAS, EPAC, RAP1, RAF1, ADCY6, and cAMP-dependent protein kinase. Our results establish a new paradigm for the mechanism of PYG activation, which depends on the type of receptor involved.Fil: Llavero, Francisco. Universidad del País Vasco; EspañaFil: Montoro, Miriam Luque. Universidad del País Vasco; EspañaFil: Sastre, Alazne Arrazola. Universidad del País Vasco; EspañaFil: Fernández Moreno, David. Universidad Europea de Madrid; España. Hospital 12 de Octubre; EspañaFil: Lacerda, Hadriano M.. Universidad del País Vasco; EspañaFil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; ArgentinaFil: Lucia, Alejandro. universidad europea de Madrid; España. Hospital 12 de Octubre; España. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Zugaza, José L.. Universidad del País Vasco; España. The Basque Foundation For Science; EspañaAmerican Society for Biochemistry and Molecular Biology2019-03-22info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/120534Llavero, Francisco; Montoro, Miriam Luque; Sastre, Alazne Arrazola; Fernández Moreno, David; Lacerda, Hadriano M.; et al.; Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 294; 12; 22-3-2019; 4345-43580021-9258CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.RA118.005997info:eu-repo/semantics/altIdentifier/url/https://www.jbc.org/content/294/12/4345info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:54:09Zoai:ri.conicet.gov.ar:11336/120534instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:54:09.812CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family |
title |
Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family |
spellingShingle |
Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family Llavero, Francisco Epidermal growth factor receptor (EGFR) RAS protein Raf kinase Cell signaling |
title_short |
Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family |
title_full |
Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family |
title_fullStr |
Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family |
title_full_unstemmed |
Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family |
title_sort |
Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family |
dc.creator.none.fl_str_mv |
Llavero, Francisco Montoro, Miriam Luque Sastre, Alazne Arrazola Fernández Moreno, David Lacerda, Hadriano M. Parada, Luis Antonio Lucia, Alejandro Zugaza, José L. |
author |
Llavero, Francisco |
author_facet |
Llavero, Francisco Montoro, Miriam Luque Sastre, Alazne Arrazola Fernández Moreno, David Lacerda, Hadriano M. Parada, Luis Antonio Lucia, Alejandro Zugaza, José L. |
author_role |
author |
author2 |
Montoro, Miriam Luque Sastre, Alazne Arrazola Fernández Moreno, David Lacerda, Hadriano M. Parada, Luis Antonio Lucia, Alejandro Zugaza, José L. |
author2_role |
author author author author author author author |
dc.subject.none.fl_str_mv |
Epidermal growth factor receptor (EGFR) RAS protein Raf kinase Cell signaling |
topic |
Epidermal growth factor receptor (EGFR) RAS protein Raf kinase Cell signaling |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
We recently uncovered a regulatory pathway of the muscle isoform of glycogen phosphorylase (PYGM) that plays an important role in regulating immune function in T cells. Here, using various enzymatic, pulldown, and immunoprecipitation assays, we describe signaling cross-talk between the small GTPases RAS and RAP1A, member of RAS oncogene family (RAP1) in human Kit 225 lymphoid cells, which, in turn, is regulated by the epidermal growth factor receptor (EGFR). We found that this communication bridge is essential for glycogen phosphorylase (PYG) activation through the canonical pathway because this enzyme is inactive in the absence of adenylyl cyclase type 6 (ADCY6). PYG activation required stimulation of both exchange protein directly activated by cAMP 2 (EPAC2) and RAP1 via RAS and ADCY6 phosphorylation, with the latter being mediated by Raf-1 proto-oncogene, Ser/ Thr kinase (RAF1). Consistent with this model, PYG activation was EGFR-dependent and may be initiated by the constitutively active form of RAS. Consequently, PYG activation in Kit 225 T cells could be blocked with specific inhibitors of RAS, EPAC, RAP1, RAF1, ADCY6, and cAMP-dependent protein kinase. Our results establish a new paradigm for the mechanism of PYG activation, which depends on the type of receptor involved. Fil: Llavero, Francisco. Universidad del País Vasco; España Fil: Montoro, Miriam Luque. Universidad del País Vasco; España Fil: Sastre, Alazne Arrazola. Universidad del País Vasco; España Fil: Fernández Moreno, David. Universidad Europea de Madrid; España. Hospital 12 de Octubre; España Fil: Lacerda, Hadriano M.. Universidad del País Vasco; España Fil: Parada, Luis Antonio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Salta. Instituto de Patología Experimental. Universidad Nacional de Salta. Facultad de Ciencias de la Salud. Instituto de Patología Experimental; Argentina Fil: Lucia, Alejandro. universidad europea de Madrid; España. Hospital 12 de Octubre; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Zugaza, José L.. Universidad del País Vasco; España. The Basque Foundation For Science; España |
description |
We recently uncovered a regulatory pathway of the muscle isoform of glycogen phosphorylase (PYGM) that plays an important role in regulating immune function in T cells. Here, using various enzymatic, pulldown, and immunoprecipitation assays, we describe signaling cross-talk between the small GTPases RAS and RAP1A, member of RAS oncogene family (RAP1) in human Kit 225 lymphoid cells, which, in turn, is regulated by the epidermal growth factor receptor (EGFR). We found that this communication bridge is essential for glycogen phosphorylase (PYG) activation through the canonical pathway because this enzyme is inactive in the absence of adenylyl cyclase type 6 (ADCY6). PYG activation required stimulation of both exchange protein directly activated by cAMP 2 (EPAC2) and RAP1 via RAS and ADCY6 phosphorylation, with the latter being mediated by Raf-1 proto-oncogene, Ser/ Thr kinase (RAF1). Consistent with this model, PYG activation was EGFR-dependent and may be initiated by the constitutively active form of RAS. Consequently, PYG activation in Kit 225 T cells could be blocked with specific inhibitors of RAS, EPAC, RAP1, RAF1, ADCY6, and cAMP-dependent protein kinase. Our results establish a new paradigm for the mechanism of PYG activation, which depends on the type of receptor involved. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-03-22 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/120534 Llavero, Francisco; Montoro, Miriam Luque; Sastre, Alazne Arrazola; Fernández Moreno, David; Lacerda, Hadriano M.; et al.; Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 294; 12; 22-3-2019; 4345-4358 0021-9258 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/120534 |
identifier_str_mv |
Llavero, Francisco; Montoro, Miriam Luque; Sastre, Alazne Arrazola; Fernández Moreno, David; Lacerda, Hadriano M.; et al.; Epidermal growth factor receptor controls glycogen phosphorylase in T cells through small GTPases of the RAS family; American Society for Biochemistry and Molecular Biology; Journal of Biological Chemistry (online); 294; 12; 22-3-2019; 4345-4358 0021-9258 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1074/jbc.RA118.005997 info:eu-repo/semantics/altIdentifier/url/https://www.jbc.org/content/294/12/4345 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
American Society for Biochemistry and Molecular Biology |
publisher.none.fl_str_mv |
American Society for Biochemistry and Molecular Biology |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613647053094912 |
score |
13.070432 |