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Binding of Ras to phosphoinositide 3-kinase p110? is required for Ras- driven tumorigenesis in mice

Binding of Ras to phosphoinositide 3-kinase p110? is required for Ras- driven tumorigenesis in mice
Binding of Ras to phosphoinositide 3-kinase p110? is required for Ras- driven tumorigenesis in mice
Ras proteins signal through direct interaction with a number of effector enzymes, including type I phosphoinositide (PI) 3-kinases. Although the ability of Ras to control PI 3-kinase has been well established in manipulated cell culture models, evidence for a role of the interaction of endogenous Ras with PI 3-kinase in normal and malignant cell growth in vivo has been lacking. Here we generate mice with mutations in the Pi3kca gene encoding the catalytic p110? isoform that block its interaction with Ras. Cells from these mice show proliferative defects and selective disruption of signaling from growth factors to PI 3-kinase. The mice display defective development of the lymphatic vasculature, resulting in perinatal appearance of chylous ascites. Most importantly, they are highly resistant to endogenous Ras oncogene-induced tumorigenesis. The interaction of Ras with p110? is thus required in vivo for certain normal growth factor signaling and for Ras-driven tumor formation.
cellbio, humdisease, signaling
0092-8674
957-968
Gupta, Surbhi
b80c9e05-e3d1-430e-a904-df175fdb7a27
Ramjaun, Antoine R.
22e4b155-e982-4cf9-9fac-808238dbf835
Haiko, Paula
d0ed3d0f-c11b-464b-8fc9-de77010a8630
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Warne, Patricia H.
8e45fb80-7807-45d7-99ab-5a10e6de5c48
Nicke, Barbara
f93266dc-717e-48ca-9134-f5e7dde1acd6
Nye, Emma
81d13b33-7d53-45e1-b667-7d1d1539411b
Stamp, Gordon
6a473650-84a6-4ca4-865c-8fc5439a69c4
Alitalo, Kari
f9470b68-4cda-43d1-b1f4-78d5e6d05d2b
Downward, Julian
11d2d3a4-5d9d-4587-9589-7c03c03958de
Gupta, Surbhi
b80c9e05-e3d1-430e-a904-df175fdb7a27
Ramjaun, Antoine R.
22e4b155-e982-4cf9-9fac-808238dbf835
Haiko, Paula
d0ed3d0f-c11b-464b-8fc9-de77010a8630
Wang, Yihua
f5044a95-60a7-42d2-87d6-5f1f789e3a7e
Warne, Patricia H.
8e45fb80-7807-45d7-99ab-5a10e6de5c48
Nicke, Barbara
f93266dc-717e-48ca-9134-f5e7dde1acd6
Nye, Emma
81d13b33-7d53-45e1-b667-7d1d1539411b
Stamp, Gordon
6a473650-84a6-4ca4-865c-8fc5439a69c4
Alitalo, Kari
f9470b68-4cda-43d1-b1f4-78d5e6d05d2b
Downward, Julian
11d2d3a4-5d9d-4587-9589-7c03c03958de

Gupta, Surbhi, Ramjaun, Antoine R., Haiko, Paula, Wang, Yihua, Warne, Patricia H., Nicke, Barbara, Nye, Emma, Stamp, Gordon, Alitalo, Kari and Downward, Julian (2007) Binding of Ras to phosphoinositide 3-kinase p110? is required for Ras- driven tumorigenesis in mice. Cell, 129 (5), 957-968. (doi:10.1016/j.cell.2007.03.051). (PMID:17540175)

Record type: Article

Abstract

Ras proteins signal through direct interaction with a number of effector enzymes, including type I phosphoinositide (PI) 3-kinases. Although the ability of Ras to control PI 3-kinase has been well established in manipulated cell culture models, evidence for a role of the interaction of endogenous Ras with PI 3-kinase in normal and malignant cell growth in vivo has been lacking. Here we generate mice with mutations in the Pi3kca gene encoding the catalytic p110? isoform that block its interaction with Ras. Cells from these mice show proliferative defects and selective disruption of signaling from growth factors to PI 3-kinase. The mice display defective development of the lymphatic vasculature, resulting in perinatal appearance of chylous ascites. Most importantly, they are highly resistant to endogenous Ras oncogene-induced tumorigenesis. The interaction of Ras with p110? is thus required in vivo for certain normal growth factor signaling and for Ras-driven tumor formation.

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More information

Accepted/In Press date: 20 March 2007
e-pub ahead of print date: 31 May 2007
Published date: 1 June 2007
Keywords: cellbio, humdisease, signaling
Organisations: Centre for Biological Sciences

Identifiers

Local EPrints ID: 385913
URI: http://eprints.soton.ac.uk/id/eprint/385913
ISSN: 0092-8674
PURE UUID: 33a8bee6-0491-4c09-a07b-0ac9a0ec6684
ORCID for Yihua Wang: ORCID iD orcid.org/0000-0001-5561-0648

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Date deposited: 26 Jan 2016 10:23
Last modified: 17 Dec 2019 01:33

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Contributors

Author: Surbhi Gupta
Author: Antoine R. Ramjaun
Author: Paula Haiko
Author: Yihua Wang ORCID iD
Author: Patricia H. Warne
Author: Barbara Nicke
Author: Emma Nye
Author: Gordon Stamp
Author: Kari Alitalo
Author: Julian Downward

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