G protein-coupled receptor-mediated activation of p110b by Gβγ is required for cellular transformation and invasiveness

Hashem A. Dbouk, Oscar Vadas, Aliaksei Shymanets, John E. Burke, Rachel S. Salamon, Bassem D. Khalil, Mathew O. Barrett, Gary L. Waldo, Chinmay Surve, Christine Hsueh, Olga Perisic, Christian Harteneck, Peter R. Shepherd, T. Kendall Harden, Alan V. Smrcka, Ronald Taussig, Anne R. Bresnick, Bernd Nürnberg, Roger L. Williams, Jonathan M. Backer

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Synergistic activation by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110β from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of p110β is specifically implicated in various physiological and pathophysiological processes, such as the growth of tumors deficient in phosphatase and tensin homolog deleted from chromosome 10 (PTEN). To determine the specific contribution of GPCR signaling to p110β-dependent functions, we identified the site in p110b that binds to the Gβγ subunit of G proteins. Mutation of this site eliminated Gβγ-dependent activation of PI3Kβ (a dimer of p110b and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide-mediated activation. Disrupting the p110β-Gβγ interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3Kb in fibroblasts and reduced the proliferation, chemotaxis, and invasiveness of PTEN-null tumor cells in culture. Our data suggest that specifically targeting GPCR signaling to PI3Kβ could provide a therapeutic approach for tumors that depend on p110β for growth and metastasis.

Original languageEnglish (US)
Article numberra89
JournalScience Signaling
Volume5
Issue number253
DOIs
StatePublished - Dec 4 2012

Fingerprint

1-Phosphatidylinositol 4-Kinase
G-Protein-Coupled Receptors
Phosphatidylinositols
Chemical activation
Tumors
Phosphotransferases
Physiological Phenomena
Null Lymphocytes
Neoplasms
Chromosomes, Human, Pair 10
Peptides
Mutation
Phosphotyrosine
Guanine Nucleotides
Receptor Protein-Tyrosine Kinases
Chemotaxis
Growth
GTP-Binding Proteins
Phosphoric Monoester Hydrolases
Carrier Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

G protein-coupled receptor-mediated activation of p110b by Gβγ is required for cellular transformation and invasiveness. / Dbouk, Hashem A.; Vadas, Oscar; Shymanets, Aliaksei; Burke, John E.; Salamon, Rachel S.; Khalil, Bassem D.; Barrett, Mathew O.; Waldo, Gary L.; Surve, Chinmay; Hsueh, Christine; Perisic, Olga; Harteneck, Christian; Shepherd, Peter R.; Harden, T. Kendall; Smrcka, Alan V.; Taussig, Ronald; Bresnick, Anne R.; Nürnberg, Bernd; Williams, Roger L.; Backer, Jonathan M.

In: Science Signaling, Vol. 5, No. 253, ra89, 04.12.2012.

Research output: Contribution to journalArticle

Dbouk, HA, Vadas, O, Shymanets, A, Burke, JE, Salamon, RS, Khalil, BD, Barrett, MO, Waldo, GL, Surve, C, Hsueh, C, Perisic, O, Harteneck, C, Shepherd, PR, Harden, TK, Smrcka, AV, Taussig, R, Bresnick, AR, Nürnberg, B, Williams, RL & Backer, JM 2012, 'G protein-coupled receptor-mediated activation of p110b by Gβγ is required for cellular transformation and invasiveness', Science Signaling, vol. 5, no. 253, ra89. https://doi.org/10.1126/scisignal.2003264
Dbouk, Hashem A. ; Vadas, Oscar ; Shymanets, Aliaksei ; Burke, John E. ; Salamon, Rachel S. ; Khalil, Bassem D. ; Barrett, Mathew O. ; Waldo, Gary L. ; Surve, Chinmay ; Hsueh, Christine ; Perisic, Olga ; Harteneck, Christian ; Shepherd, Peter R. ; Harden, T. Kendall ; Smrcka, Alan V. ; Taussig, Ronald ; Bresnick, Anne R. ; Nürnberg, Bernd ; Williams, Roger L. ; Backer, Jonathan M. / G protein-coupled receptor-mediated activation of p110b by Gβγ is required for cellular transformation and invasiveness. In: Science Signaling. 2012 ; Vol. 5, No. 253.
@article{8ef0e1226743487fbbf62a6e79dd0a62,
title = "G protein-coupled receptor-mediated activation of p110b by Gβγ is required for cellular transformation and invasiveness",
abstract = "Synergistic activation by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110β from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of p110β is specifically implicated in various physiological and pathophysiological processes, such as the growth of tumors deficient in phosphatase and tensin homolog deleted from chromosome 10 (PTEN). To determine the specific contribution of GPCR signaling to p110β-dependent functions, we identified the site in p110b that binds to the Gβγ subunit of G proteins. Mutation of this site eliminated Gβγ-dependent activation of PI3Kβ (a dimer of p110b and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide-mediated activation. Disrupting the p110β-Gβγ interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3Kb in fibroblasts and reduced the proliferation, chemotaxis, and invasiveness of PTEN-null tumor cells in culture. Our data suggest that specifically targeting GPCR signaling to PI3Kβ could provide a therapeutic approach for tumors that depend on p110β for growth and metastasis.",
author = "Dbouk, {Hashem A.} and Oscar Vadas and Aliaksei Shymanets and Burke, {John E.} and Salamon, {Rachel S.} and Khalil, {Bassem D.} and Barrett, {Mathew O.} and Waldo, {Gary L.} and Chinmay Surve and Christine Hsueh and Olga Perisic and Christian Harteneck and Shepherd, {Peter R.} and Harden, {T. Kendall} and Smrcka, {Alan V.} and Ronald Taussig and Bresnick, {Anne R.} and Bernd N{\"u}rnberg and Williams, {Roger L.} and Backer, {Jonathan M.}",
year = "2012",
month = "12",
day = "4",
doi = "10.1126/scisignal.2003264",
language = "English (US)",
volume = "5",
journal = "Science Signaling",
issn = "1937-9145",
publisher = "American Association for the Advancement of Science",
number = "253",

}

TY - JOUR

T1 - G protein-coupled receptor-mediated activation of p110b by Gβγ is required for cellular transformation and invasiveness

AU - Dbouk, Hashem A.

AU - Vadas, Oscar

AU - Shymanets, Aliaksei

AU - Burke, John E.

AU - Salamon, Rachel S.

AU - Khalil, Bassem D.

AU - Barrett, Mathew O.

AU - Waldo, Gary L.

AU - Surve, Chinmay

AU - Hsueh, Christine

AU - Perisic, Olga

AU - Harteneck, Christian

AU - Shepherd, Peter R.

AU - Harden, T. Kendall

AU - Smrcka, Alan V.

AU - Taussig, Ronald

AU - Bresnick, Anne R.

AU - Nürnberg, Bernd

AU - Williams, Roger L.

AU - Backer, Jonathan M.

PY - 2012/12/4

Y1 - 2012/12/4

N2 - Synergistic activation by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110β from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of p110β is specifically implicated in various physiological and pathophysiological processes, such as the growth of tumors deficient in phosphatase and tensin homolog deleted from chromosome 10 (PTEN). To determine the specific contribution of GPCR signaling to p110β-dependent functions, we identified the site in p110b that binds to the Gβγ subunit of G proteins. Mutation of this site eliminated Gβγ-dependent activation of PI3Kβ (a dimer of p110b and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide-mediated activation. Disrupting the p110β-Gβγ interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3Kb in fibroblasts and reduced the proliferation, chemotaxis, and invasiveness of PTEN-null tumor cells in culture. Our data suggest that specifically targeting GPCR signaling to PI3Kβ could provide a therapeutic approach for tumors that depend on p110β for growth and metastasis.

AB - Synergistic activation by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110β from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of p110β is specifically implicated in various physiological and pathophysiological processes, such as the growth of tumors deficient in phosphatase and tensin homolog deleted from chromosome 10 (PTEN). To determine the specific contribution of GPCR signaling to p110β-dependent functions, we identified the site in p110b that binds to the Gβγ subunit of G proteins. Mutation of this site eliminated Gβγ-dependent activation of PI3Kβ (a dimer of p110b and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide-mediated activation. Disrupting the p110β-Gβγ interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3Kb in fibroblasts and reduced the proliferation, chemotaxis, and invasiveness of PTEN-null tumor cells in culture. Our data suggest that specifically targeting GPCR signaling to PI3Kβ could provide a therapeutic approach for tumors that depend on p110β for growth and metastasis.

UR - http://www.scopus.com/inward/record.url?scp=84870750816&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870750816&partnerID=8YFLogxK

U2 - 10.1126/scisignal.2003264

DO - 10.1126/scisignal.2003264

M3 - Article

VL - 5

JO - Science Signaling

JF - Science Signaling

SN - 1937-9145

IS - 253

M1 - ra89

ER -