FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma

Autores
Cooke, Mariana; Kreider Letterman, Gabriel; Baker, Martin James; Zhang, Suli; Sullivan, Neil T.; Eruslanov, Evgeniy; Abba, Martín Carlos; Goicoechea, Silvia M.; Garcia Mata, Rafael; Kazanietz, Marcelo Gabriel
Año de publicación
2021
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Despite the undisputable role of the small GTPase Rac1 in the regulation of actin cytoskeleton reorganization, the Rac guanine-nucleotide exchange factors (Rac-GEFs) involved in Rac1-mediated motility and invasion in human lung adenocarcinoma cells remain largely unknown. Here, we identify FARP1, ARHGEF39, and TIAM2 as essential Rac-GEFs responsible for Rac1-mediated lung cancer cell migration upon EGFR and c-Met activation. Noteworthily, these Rac-GEFs operate in a non-redundant manner by controlling distinctive aspects of ruffle dynamics formation. Mechanistic analysis reveals a leading role of the AXL-Gab1-PI3K axis in conferring pro-motility traits downstream of EGFR. Along with the positive association between the overexpression of Rac-GEFs and poor lung adenocarcinoma patient survival, we show that FARP1 and ARHGEF39 are upregulated in EpCam+ cells sorted from primary human lung adenocarcinomas. Overall, our study reveals fundamental insights into the complex intricacies underlying Rac-GEF-mediated cancer cell motility signaling, hence underscoring promising targets for metastatic lung cancer therapy.
Fil: Cooke, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. University of Pennsylvania; Estados Unidos
Fil: Kreider Letterman, Gabriel. University Of Toledo (utoledo); Estados Unidos
Fil: Baker, Martin James. University of Pennsylvania; Estados Unidos
Fil: Zhang, Suli. University of Pennsylvania; Estados Unidos
Fil: Sullivan, Neil T.. University of Pennsylvania; Estados Unidos
Fil: Eruslanov, Evgeniy. University of Pennsylvania; Estados Unidos
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Goicoechea, Silvia M.. University Of Toledo (utoledo); Estados Unidos
Fil: Garcia Mata, Rafael. University Of Toledo (utoledo); Estados Unidos
Fil: Kazanietz, Marcelo Gabriel. University of Pennsylvania; Estados Unidos
Materia
ARHGEF39
AXL
EGFR
FARP1
LUNG CANCER
MIGRATION
RAC-GEF
RAC1
RUFFLES
TIAM2
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/150901
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/150901
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinomaCooke, MarianaKreider Letterman, GabrielBaker, Martin JamesZhang, SuliSullivan, Neil T.Eruslanov, EvgeniyAbba, Martín CarlosGoicoechea, Silvia M.Garcia Mata, RafaelKazanietz, Marcelo GabrielARHGEF39AXLEGFRFARP1LUNG CANCERMIGRATIONRAC-GEFRAC1RUFFLESTIAM2https://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Despite the undisputable role of the small GTPase Rac1 in the regulation of actin cytoskeleton reorganization, the Rac guanine-nucleotide exchange factors (Rac-GEFs) involved in Rac1-mediated motility and invasion in human lung adenocarcinoma cells remain largely unknown. Here, we identify FARP1, ARHGEF39, and TIAM2 as essential Rac-GEFs responsible for Rac1-mediated lung cancer cell migration upon EGFR and c-Met activation. Noteworthily, these Rac-GEFs operate in a non-redundant manner by controlling distinctive aspects of ruffle dynamics formation. Mechanistic analysis reveals a leading role of the AXL-Gab1-PI3K axis in conferring pro-motility traits downstream of EGFR. Along with the positive association between the overexpression of Rac-GEFs and poor lung adenocarcinoma patient survival, we show that FARP1 and ARHGEF39 are upregulated in EpCam+ cells sorted from primary human lung adenocarcinomas. Overall, our study reveals fundamental insights into the complex intricacies underlying Rac-GEF-mediated cancer cell motility signaling, hence underscoring promising targets for metastatic lung cancer therapy.Fil: Cooke, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. University of Pennsylvania; Estados UnidosFil: Kreider Letterman, Gabriel. University Of Toledo (utoledo); Estados UnidosFil: Baker, Martin James. University of Pennsylvania; Estados UnidosFil: Zhang, Suli. University of Pennsylvania; Estados UnidosFil: Sullivan, Neil T.. University of Pennsylvania; Estados UnidosFil: Eruslanov, Evgeniy. University of Pennsylvania; Estados UnidosFil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Goicoechea, Silvia M.. University Of Toledo (utoledo); Estados UnidosFil: Garcia Mata, Rafael. University Of Toledo (utoledo); Estados UnidosFil: Kazanietz, Marcelo Gabriel. University of Pennsylvania; Estados UnidosElsevier2021-11info: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/11336/150901Cooke, Mariana; Kreider Letterman, Gabriel; Baker, Martin James; Zhang, Suli; Sullivan, Neil T.; et al.; FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma; Elsevier; Cell Reports; 37; 5; 11-2021; 1-242211-1247CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.celrep.2021.109905info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2211124721013759?via%3Dihubinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:34:05Zoai:ri.conicet.gov.ar:11336/150901instacron: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 10:34:06.013CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma
title FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma
spellingShingle FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma
Cooke, Mariana
ARHGEF39
AXL
EGFR
FARP1
LUNG CANCER
MIGRATION
RAC-GEF
RAC1
RUFFLES
TIAM2
title_short FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma
title_full FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma
title_fullStr FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma
title_full_unstemmed FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma
title_sort FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma
dc.creator.none.fl_str_mv Cooke, Mariana
Kreider Letterman, Gabriel
Baker, Martin James
Zhang, Suli
Sullivan, Neil T.
Eruslanov, Evgeniy
Abba, Martín Carlos
Goicoechea, Silvia M.
Garcia Mata, Rafael
Kazanietz, Marcelo Gabriel
author Cooke, Mariana
author_facet Cooke, Mariana
Kreider Letterman, Gabriel
Baker, Martin James
Zhang, Suli
Sullivan, Neil T.
Eruslanov, Evgeniy
Abba, Martín Carlos
Goicoechea, Silvia M.
Garcia Mata, Rafael
Kazanietz, Marcelo Gabriel
author_role author
author2 Kreider Letterman, Gabriel
Baker, Martin James
Zhang, Suli
Sullivan, Neil T.
Eruslanov, Evgeniy
Abba, Martín Carlos
Goicoechea, Silvia M.
Garcia Mata, Rafael
Kazanietz, Marcelo Gabriel
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ARHGEF39
AXL
EGFR
FARP1
LUNG CANCER
MIGRATION
RAC-GEF
RAC1
RUFFLES
TIAM2
topic ARHGEF39
AXL
EGFR
FARP1
LUNG CANCER
MIGRATION
RAC-GEF
RAC1
RUFFLES
TIAM2
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Despite the undisputable role of the small GTPase Rac1 in the regulation of actin cytoskeleton reorganization, the Rac guanine-nucleotide exchange factors (Rac-GEFs) involved in Rac1-mediated motility and invasion in human lung adenocarcinoma cells remain largely unknown. Here, we identify FARP1, ARHGEF39, and TIAM2 as essential Rac-GEFs responsible for Rac1-mediated lung cancer cell migration upon EGFR and c-Met activation. Noteworthily, these Rac-GEFs operate in a non-redundant manner by controlling distinctive aspects of ruffle dynamics formation. Mechanistic analysis reveals a leading role of the AXL-Gab1-PI3K axis in conferring pro-motility traits downstream of EGFR. Along with the positive association between the overexpression of Rac-GEFs and poor lung adenocarcinoma patient survival, we show that FARP1 and ARHGEF39 are upregulated in EpCam+ cells sorted from primary human lung adenocarcinomas. Overall, our study reveals fundamental insights into the complex intricacies underlying Rac-GEF-mediated cancer cell motility signaling, hence underscoring promising targets for metastatic lung cancer therapy.
Fil: Cooke, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentina. University of Pennsylvania; Estados Unidos
Fil: Kreider Letterman, Gabriel. University Of Toledo (utoledo); Estados Unidos
Fil: Baker, Martin James. University of Pennsylvania; Estados Unidos
Fil: Zhang, Suli. University of Pennsylvania; Estados Unidos
Fil: Sullivan, Neil T.. University of Pennsylvania; Estados Unidos
Fil: Eruslanov, Evgeniy. University of Pennsylvania; Estados Unidos
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Goicoechea, Silvia M.. University Of Toledo (utoledo); Estados Unidos
Fil: Garcia Mata, Rafael. University Of Toledo (utoledo); Estados Unidos
Fil: Kazanietz, Marcelo Gabriel. University of Pennsylvania; Estados Unidos
description Despite the undisputable role of the small GTPase Rac1 in the regulation of actin cytoskeleton reorganization, the Rac guanine-nucleotide exchange factors (Rac-GEFs) involved in Rac1-mediated motility and invasion in human lung adenocarcinoma cells remain largely unknown. Here, we identify FARP1, ARHGEF39, and TIAM2 as essential Rac-GEFs responsible for Rac1-mediated lung cancer cell migration upon EGFR and c-Met activation. Noteworthily, these Rac-GEFs operate in a non-redundant manner by controlling distinctive aspects of ruffle dynamics formation. Mechanistic analysis reveals a leading role of the AXL-Gab1-PI3K axis in conferring pro-motility traits downstream of EGFR. Along with the positive association between the overexpression of Rac-GEFs and poor lung adenocarcinoma patient survival, we show that FARP1 and ARHGEF39 are upregulated in EpCam+ cells sorted from primary human lung adenocarcinomas. Overall, our study reveals fundamental insights into the complex intricacies underlying Rac-GEF-mediated cancer cell motility signaling, hence underscoring promising targets for metastatic lung cancer therapy.
publishDate 2021
dc.date.none.fl_str_mv 2021-11
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/11336/150901
Cooke, Mariana; Kreider Letterman, Gabriel; Baker, Martin James; Zhang, Suli; Sullivan, Neil T.; et al.; FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma; Elsevier; Cell Reports; 37; 5; 11-2021; 1-24
2211-1247
CONICET Digital
CONICET
url http://hdl.handle.net/11336/150901
identifier_str_mv Cooke, Mariana; Kreider Letterman, Gabriel; Baker, Martin James; Zhang, Suli; Sullivan, Neil T.; et al.; FARP1, ARHGEF39, and TIAM2 are essential receptor tyrosine kinase effectors for Rac1-dependent cell motility in human lung adenocarcinoma; Elsevier; Cell Reports; 37; 5; 11-2021; 1-24
2211-1247
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1016/j.celrep.2021.109905
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S2211124721013759?via%3Dihub
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
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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score 13.070432

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