α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling

Landon J. Inge, Sigrid A. Rajasekaran, Daniel Wolle, Sonali P. Barwe, Sergey Ryazantsev, Charles M. Ewing, William B Isaacs, Ayyappan K. Rajasekaran

Research output: Contribution to journalArticle

Abstract

Loss of α-catenin is one of the characteristics of prostate cancer. The catenins (α and β) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of β-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where β-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, β-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of β-catenin invariably are altered in cancer. Although a wealth of information is available about β-catenin deregulation during oncogenesis, much less is known about how or whether α-catenin regulates β-catenin functions. In this study, we show that α-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of β-catenin. In α-catenin-null prostate cancer cells, reexpression of α-catenin increased cell-cell adhesion and decreased β-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of β-catenin is a major mechanism for decreased β-catenin interaction with E-cadherin in α-catenin-null cells. α-Catenin attenuated the effect of Src phosphorylation by increasing β-catenin association with E-cadherin. We also show that α-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that α-catenin is a key regulator of β-catenin transcriptional activity and that the status of α-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.

Original languageEnglish (US)
Pages (from-to)1386-1397
Number of pages12
JournalMolecular Cancer Therapeutics
Volume7
Issue number6
DOIs
StatePublished - 2008

Fingerprint

Catenins
Cadherins
Cell Adhesion
Cell Proliferation
Prostatic Neoplasms
Phosphorylation
Tyrosine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

Cite this

Inge, L. J., Rajasekaran, S. A., Wolle, D., Barwe, S. P., Ryazantsev, S., Ewing, C. M., ... Rajasekaran, A. K. (2008). α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling. Molecular Cancer Therapeutics, 7(6), 1386-1397. https://doi.org/10.1158/1535-7163.MCT-07-2029

α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling. / Inge, Landon J.; Rajasekaran, Sigrid A.; Wolle, Daniel; Barwe, Sonali P.; Ryazantsev, Sergey; Ewing, Charles M.; Isaacs, William B; Rajasekaran, Ayyappan K.

In: Molecular Cancer Therapeutics, Vol. 7, No. 6, 2008, p. 1386-1397.

Research output: Contribution to journalArticle

Inge, LJ, Rajasekaran, SA, Wolle, D, Barwe, SP, Ryazantsev, S, Ewing, CM, Isaacs, WB & Rajasekaran, AK 2008, 'α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling', Molecular Cancer Therapeutics, vol. 7, no. 6, pp. 1386-1397. https://doi.org/10.1158/1535-7163.MCT-07-2029
Inge, Landon J. ; Rajasekaran, Sigrid A. ; Wolle, Daniel ; Barwe, Sonali P. ; Ryazantsev, Sergey ; Ewing, Charles M. ; Isaacs, William B ; Rajasekaran, Ayyappan K. / α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling. In: Molecular Cancer Therapeutics. 2008 ; Vol. 7, No. 6. pp. 1386-1397.
@article{8b092fa7ee1041dea205d63a96ac04dd,
title = "α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling",
abstract = "Loss of α-catenin is one of the characteristics of prostate cancer. The catenins (α and β) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of β-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where β-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, β-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of β-catenin invariably are altered in cancer. Although a wealth of information is available about β-catenin deregulation during oncogenesis, much less is known about how or whether α-catenin regulates β-catenin functions. In this study, we show that α-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of β-catenin. In α-catenin-null prostate cancer cells, reexpression of α-catenin increased cell-cell adhesion and decreased β-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of β-catenin is a major mechanism for decreased β-catenin interaction with E-cadherin in α-catenin-null cells. α-Catenin attenuated the effect of Src phosphorylation by increasing β-catenin association with E-cadherin. We also show that α-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that α-catenin is a key regulator of β-catenin transcriptional activity and that the status of α-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.",
author = "Inge, {Landon J.} and Rajasekaran, {Sigrid A.} and Daniel Wolle and Barwe, {Sonali P.} and Sergey Ryazantsev and Ewing, {Charles M.} and Isaacs, {William B} and Rajasekaran, {Ayyappan K.}",
year = "2008",
doi = "10.1158/1535-7163.MCT-07-2029",
language = "English (US)",
volume = "7",
pages = "1386--1397",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

TY - JOUR

T1 - α-Catenin overrides Src-dependent activation of β-catenin oncogenic signaling

AU - Inge, Landon J.

AU - Rajasekaran, Sigrid A.

AU - Wolle, Daniel

AU - Barwe, Sonali P.

AU - Ryazantsev, Sergey

AU - Ewing, Charles M.

AU - Isaacs, William B

AU - Rajasekaran, Ayyappan K.

PY - 2008

Y1 - 2008

N2 - Loss of α-catenin is one of the characteristics of prostate cancer. The catenins (α and β) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of β-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where β-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, β-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of β-catenin invariably are altered in cancer. Although a wealth of information is available about β-catenin deregulation during oncogenesis, much less is known about how or whether α-catenin regulates β-catenin functions. In this study, we show that α-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of β-catenin. In α-catenin-null prostate cancer cells, reexpression of α-catenin increased cell-cell adhesion and decreased β-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of β-catenin is a major mechanism for decreased β-catenin interaction with E-cadherin in α-catenin-null cells. α-Catenin attenuated the effect of Src phosphorylation by increasing β-catenin association with E-cadherin. We also show that α-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that α-catenin is a key regulator of β-catenin transcriptional activity and that the status of α-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.

AB - Loss of α-catenin is one of the characteristics of prostate cancer. The catenins (α and β) associated with E-cadherin play a critical role in the regulation of cell-cell adhesion. Tyrosine phosphorylation of β-catenin dissociates it from E-cadherin and facilitates its entry into the nucleus, where β-catenin acts as a transcriptional activator inducing genes involved in cell proliferation. Thus, β-catenin regulates cell-cell adhesion and cell proliferation. Mechanisms controlling the balance between these functions of β-catenin invariably are altered in cancer. Although a wealth of information is available about β-catenin deregulation during oncogenesis, much less is known about how or whether α-catenin regulates β-catenin functions. In this study, we show that α-catenin acts as a switch regulating the cell-cell adhesion and proliferation functions of β-catenin. In α-catenin-null prostate cancer cells, reexpression of α-catenin increased cell-cell adhesion and decreased β-catenin transcriptional activity, cyclin D1 levels, and cell proliferation. Further, Src-mediated tyrosine phosphorylation of β-catenin is a major mechanism for decreased β-catenin interaction with E-cadherin in α-catenin-null cells. α-Catenin attenuated the effect of Src phosphorylation by increasing β-catenin association with E-cadherin. We also show that α-catenin increases the sensitivity of prostate cancer cells to a Src inhibitor in suppressing cell proliferation. This study reveals for the first time that α-catenin is a key regulator of β-catenin transcriptional activity and that the status of α-catenin expression in tumor tissues might have prognostic value for Src targeted therapy.

UR - http://www.scopus.com/inward/record.url?scp=49849087482&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=49849087482&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-07-2029

DO - 10.1158/1535-7163.MCT-07-2029

M3 - Article

VL - 7

SP - 1386

EP - 1397

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 6

ER -