GPCR signaling mediates tumor metastasis via PI3Kβ

Bassem D. Khalil, Christine Hsueh, Yanyan Cao, Widian F Abi Saab, Yarong Wang, John S. Condeelis, Anne R. Bresnick, Jonathan M. Backer

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Ka, a role for PI3Kα has begun to emerge. The PI3Kβ isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein- coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolishes PI3Kβ binding to Gβγ (p110526KK-DD). Expression of this mutant in p110β-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCRs and PI3Kβ in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease.

Original languageEnglish (US)
Pages (from-to)2944-2953
Number of pages10
JournalCancer Research
Volume76
Issue number10
DOIs
StatePublished - May 15 2016

Fingerprint

G-Protein-Coupled Receptors
Phosphatidylinositol 3-Kinases
Neoplasm Metastasis
Neoplasms
Receptor Protein-Tyrosine Kinases
Protein Isoforms
Carcinogenesis
Breast
Breast Neoplasms
Mutation
Enzymes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

GPCR signaling mediates tumor metastasis via PI3Kβ. / Khalil, Bassem D.; Hsueh, Christine; Cao, Yanyan; Saab, Widian F Abi; Wang, Yarong; Condeelis, John S.; Bresnick, Anne R.; Backer, Jonathan M.

In: Cancer Research, Vol. 76, No. 10, 15.05.2016, p. 2944-2953.

Research output: Contribution to journalArticle

Khalil BD, Hsueh C, Cao Y, Saab WFA, Wang Y, Condeelis JS et al. GPCR signaling mediates tumor metastasis via PI3Kβ. Cancer Research. 2016 May 15;76(10):2944-2953. https://doi.org/10.1158/0008-5472.CAN-15-1675
Khalil, Bassem D. ; Hsueh, Christine ; Cao, Yanyan ; Saab, Widian F Abi ; Wang, Yarong ; Condeelis, John S. ; Bresnick, Anne R. ; Backer, Jonathan M. / GPCR signaling mediates tumor metastasis via PI3Kβ. In: Cancer Research. 2016 ; Vol. 76, No. 10. pp. 2944-2953.
@article{c49a6a2baed24e23b88769ef666a5e93,
title = "GPCR signaling mediates tumor metastasis via PI3Kβ",
abstract = "Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Ka, a role for PI3Kα has begun to emerge. The PI3Kβ isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein- coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolishes PI3Kβ binding to Gβγ (p110526KK-DD). Expression of this mutant in p110β-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCRs and PI3Kβ in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease.",
author = "Khalil, {Bassem D.} and Christine Hsueh and Yanyan Cao and Saab, {Widian F Abi} and Yarong Wang and Condeelis, {John S.} and Bresnick, {Anne R.} and Backer, {Jonathan M.}",
year = "2016",
month = "5",
day = "15",
doi = "10.1158/0008-5472.CAN-15-1675",
language = "English (US)",
volume = "76",
pages = "2944--2953",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "10",

}

TY - JOUR

T1 - GPCR signaling mediates tumor metastasis via PI3Kβ

AU - Khalil, Bassem D.

AU - Hsueh, Christine

AU - Cao, Yanyan

AU - Saab, Widian F Abi

AU - Wang, Yarong

AU - Condeelis, John S.

AU - Bresnick, Anne R.

AU - Backer, Jonathan M.

PY - 2016/5/15

Y1 - 2016/5/15

N2 - Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Ka, a role for PI3Kα has begun to emerge. The PI3Kβ isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein- coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolishes PI3Kβ binding to Gβγ (p110526KK-DD). Expression of this mutant in p110β-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCRs and PI3Kβ in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease.

AB - Inappropriate activation of PI3K signaling has been implicated strongly in human cancer. Although studies on the role of PI3K signaling in breast tumorigenesis and progression have focused most intensively on PI3Ka, a role for PI3Kα has begun to emerge. The PI3Kβ isoform is unique among class IA PI3K enzymes in that it is activated by both receptor tyrosine kinases and G-protein- coupled receptors (GPCR). In previous work, we identified a mutation that specifically abolishes PI3Kβ binding to Gβγ (p110526KK-DD). Expression of this mutant in p110β-silenced breast cancer cells inhibits multiple steps of the metastatic cascade in vitro and in vivo and causes a cell autonomous defect in invadopodial matrix degradation. Our results identify a novel link between GPCRs and PI3Kβ in mediating metastasis, suggesting that disruption of this link might offer a novel therapeutic target to prevent the development of metastatic disease.

UR - http://www.scopus.com/inward/record.url?scp=84971516907&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84971516907&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-15-1675

DO - 10.1158/0008-5472.CAN-15-1675

M3 - Article

C2 - 27013201

AN - SCOPUS:84971516907

VL - 76

SP - 2944

EP - 2953

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 10

ER -