A ras signaling complex controls the RasC-TORC2 pathway and directed cell migration

Pascale G. Charest; Zhouxin Shen; Ashley Lakoduk; Atsuo T. Sasaki; Steven P. Briggs; Richard A. Firtel

doi:10.1016/j.devcel.2010.03.017

A ras signaling complex controls the RasC-TORC2 pathway and directed cell migration

Pascale G. Charest, Zhouxin Shen, Ashley Lakoduk, Atsuo T. Sasaki, Steven P. Briggs, Richard A. Firtel

Research output: Contribution to journal › Article › peer-review

124 Scopus citations

Abstract

Ras was found to regulate Dictyostelium chemotaxis, but the mechanisms that spatially and temporally control Ras activity during chemotaxis remain largely unknown. We report the discovery of a Ras signaling complex that includes the Ras guanine exchange factor (RasGEF) Aimless, RasGEFH, protein phosphatase 2A (PP2A), and a scaffold designated Sca1. The Sca1/RasGEF/PP2A complex is recruited to the plasma membrane in a chemoattractant- and F-actin-dependent manner and is enriched at the leading edge of chemotaxing cells where it regulates F-actin dynamics and signal relay by controlling the activation of RasC and the downstream target of rapamycin complex 2 (TORC2)-Akt/protein kinase B (PKB) pathway. In addition, PKB and PKB-related PKBR1 phosphorylate Sca1 and regulate the membrane localization of the Sca1/RasGEF/PP2A complex, and thereby RasC activity, in a negative feedback fashion. Thus, our study uncovered a molecular mechanism whereby RasC activity and the spatiotemporal activation of TORC2 are tightly controlled at the leading edge of chemotaxing cells.

Original language	English (US)
Pages (from-to)	737-749
Number of pages	13
Journal	Developmental Cell
Volume	18
Issue number	5
DOIs	https://doi.org/10.1016/j.devcel.2010.03.017
State	Published - May 2010
Externally published	Yes

Keywords

Cellbio
Signaling

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

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10.1016/j.devcel.2010.03.017

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@article{75470090047843ef855787a265fcc8b3,

title = "A ras signaling complex controls the RasC-TORC2 pathway and directed cell migration",

abstract = "Ras was found to regulate Dictyostelium chemotaxis, but the mechanisms that spatially and temporally control Ras activity during chemotaxis remain largely unknown. We report the discovery of a Ras signaling complex that includes the Ras guanine exchange factor (RasGEF) Aimless, RasGEFH, protein phosphatase 2A (PP2A), and a scaffold designated Sca1. The Sca1/RasGEF/PP2A complex is recruited to the plasma membrane in a chemoattractant- and F-actin-dependent manner and is enriched at the leading edge of chemotaxing cells where it regulates F-actin dynamics and signal relay by controlling the activation of RasC and the downstream target of rapamycin complex 2 (TORC2)-Akt/protein kinase B (PKB) pathway. In addition, PKB and PKB-related PKBR1 phosphorylate Sca1 and regulate the membrane localization of the Sca1/RasGEF/PP2A complex, and thereby RasC activity, in a negative feedback fashion. Thus, our study uncovered a molecular mechanism whereby RasC activity and the spatiotemporal activation of TORC2 are tightly controlled at the leading edge of chemotaxing cells.",

keywords = "Cellbio, Signaling",

author = "Charest, {Pascale G.} and Zhouxin Shen and Ashley Lakoduk and Sasaki, {Atsuo T.} and Briggs, {Steven P.} and Firtel, {Richard A.}",

note = "Funding Information: We thank the Firtel laboratory members for their technical support, constructive discussions, and critical reading of the manuscript; C. Janetopoulos for sharing his protocol on preparation and folate stimulation of vegetative cells; and H. Hakozaki and O. Kwon for assistance with TIRF imaging, which was conducted at the National Center for Microscopy and Imaging Research at the University of California, San Diego, supported by National Institutes of Health Research Resource Grant P41 RR04050 to M. Ellisman. P.G.C. was supported, in part, by a fellowship from the Fonds de la Recherche en Sant{\'e} du Qu{\'e}bec. This work was supported by USPS grant R01 GM037830 to R.A.F. and P01 GM078586. ",

year = "2010",

month = may,

doi = "10.1016/j.devcel.2010.03.017",

language = "English (US)",

volume = "18",

pages = "737--749",

journal = "Developmental Cell",

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publisher = "Cell Press",

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TY - JOUR

T1 - A ras signaling complex controls the RasC-TORC2 pathway and directed cell migration

AU - Charest, Pascale G.

AU - Shen, Zhouxin

AU - Lakoduk, Ashley

AU - Sasaki, Atsuo T.

AU - Briggs, Steven P.

AU - Firtel, Richard A.

N1 - Funding Information: We thank the Firtel laboratory members for their technical support, constructive discussions, and critical reading of the manuscript; C. Janetopoulos for sharing his protocol on preparation and folate stimulation of vegetative cells; and H. Hakozaki and O. Kwon for assistance with TIRF imaging, which was conducted at the National Center for Microscopy and Imaging Research at the University of California, San Diego, supported by National Institutes of Health Research Resource Grant P41 RR04050 to M. Ellisman. P.G.C. was supported, in part, by a fellowship from the Fonds de la Recherche en Santé du Québec. This work was supported by USPS grant R01 GM037830 to R.A.F. and P01 GM078586.

PY - 2010/5

Y1 - 2010/5

N2 - Ras was found to regulate Dictyostelium chemotaxis, but the mechanisms that spatially and temporally control Ras activity during chemotaxis remain largely unknown. We report the discovery of a Ras signaling complex that includes the Ras guanine exchange factor (RasGEF) Aimless, RasGEFH, protein phosphatase 2A (PP2A), and a scaffold designated Sca1. The Sca1/RasGEF/PP2A complex is recruited to the plasma membrane in a chemoattractant- and F-actin-dependent manner and is enriched at the leading edge of chemotaxing cells where it regulates F-actin dynamics and signal relay by controlling the activation of RasC and the downstream target of rapamycin complex 2 (TORC2)-Akt/protein kinase B (PKB) pathway. In addition, PKB and PKB-related PKBR1 phosphorylate Sca1 and regulate the membrane localization of the Sca1/RasGEF/PP2A complex, and thereby RasC activity, in a negative feedback fashion. Thus, our study uncovered a molecular mechanism whereby RasC activity and the spatiotemporal activation of TORC2 are tightly controlled at the leading edge of chemotaxing cells.

AB - Ras was found to regulate Dictyostelium chemotaxis, but the mechanisms that spatially and temporally control Ras activity during chemotaxis remain largely unknown. We report the discovery of a Ras signaling complex that includes the Ras guanine exchange factor (RasGEF) Aimless, RasGEFH, protein phosphatase 2A (PP2A), and a scaffold designated Sca1. The Sca1/RasGEF/PP2A complex is recruited to the plasma membrane in a chemoattractant- and F-actin-dependent manner and is enriched at the leading edge of chemotaxing cells where it regulates F-actin dynamics and signal relay by controlling the activation of RasC and the downstream target of rapamycin complex 2 (TORC2)-Akt/protein kinase B (PKB) pathway. In addition, PKB and PKB-related PKBR1 phosphorylate Sca1 and regulate the membrane localization of the Sca1/RasGEF/PP2A complex, and thereby RasC activity, in a negative feedback fashion. Thus, our study uncovered a molecular mechanism whereby RasC activity and the spatiotemporal activation of TORC2 are tightly controlled at the leading edge of chemotaxing cells.

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JO - Developmental Cell

JF - Developmental Cell

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ER -

A ras signaling complex controls the RasC-TORC2 pathway and directed cell migration

Abstract

Keywords

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