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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/120534
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/120534
network_acronym_str CONICETDig
repository_id_str 3498
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 Técnicas2025-10-15T14:49:05Zoai: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:34982025-10-15 14:49:05.931CONICET 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
_version_ 1846083012777738240
score 13.22299

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