Phosphorylation of MUC1 by met modulates interaction with p53 and MMP1 expression

Pankaj Singh, Michelle E. Behrens, John P. Eggers, Ronald Cerny, Jennifer M. Bailey, Kandavel Shanmugam, Sandra J. Gendler, Eric P. Bennett, Michael A Hollingsworth

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

MUC1, a transmembrane mucin, is a key modulator of several signaling pathways that affect oncogenesis, motility, and cell morphology. The interaction of MUC1 cytoplasmic tail (MUC1CT) with signal transducers and its nuclear translocation and subsequent biological responses are believed to be regulated by phosphorylation status, but the precise mechanisms by which this occurs remain poorly defined. We detected a novel association between the Met receptor tyrosine kinase and the MUC1CT. Met catalyzed phosphorylation of tyrosine at YHPM in the MUC1CT. Stimulation of S2-013.MUC1F pancreatic cancer cells with hepatocyte growth factor facilitated nuclear localization of MUC1CT, as determined by real time confocal imaging analysis. MUC1 overexpression also facilitated faster turnover of Met. Phosphorylation of MUC1CT by Met enhanced its interaction with p53, which led to suppression of AP1 transcription factor activity through interactions at the MMP1 promoter, ultimately leading to reduced transcription of MMP1. This correlated with a decrease in hepatocyte growth factor-induced invasiveness when MUC1 was overexpressed. The results demonstrate that MUC1 modulates Met-mediated oncogenic signaling in cancer.

Original languageEnglish (US)
Pages (from-to)26985-26995
Number of pages11
JournalJournal of Biological Chemistry
Volume283
Issue number40
DOIs
StatePublished - Oct 3 2008

Fingerprint

Phosphorylation
Hepatocyte Growth Factor
Receptor Protein-Tyrosine Kinases
Mucins
Transcription
Transducers
Pancreatic Neoplasms
Modulators
Cell Movement
Tyrosine
Carcinogenesis
Transcription Factors
Cells
Association reactions
Imaging techniques
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Phosphorylation of MUC1 by met modulates interaction with p53 and MMP1 expression. / Singh, Pankaj; Behrens, Michelle E.; Eggers, John P.; Cerny, Ronald; Bailey, Jennifer M.; Shanmugam, Kandavel; Gendler, Sandra J.; Bennett, Eric P.; Hollingsworth, Michael A.

In: Journal of Biological Chemistry, Vol. 283, No. 40, 03.10.2008, p. 26985-26995.

Research output: Contribution to journalArticle

Singh, Pankaj ; Behrens, Michelle E. ; Eggers, John P. ; Cerny, Ronald ; Bailey, Jennifer M. ; Shanmugam, Kandavel ; Gendler, Sandra J. ; Bennett, Eric P. ; Hollingsworth, Michael A. / Phosphorylation of MUC1 by met modulates interaction with p53 and MMP1 expression. In: Journal of Biological Chemistry. 2008 ; Vol. 283, No. 40. pp. 26985-26995.
@article{46f5442c3f4e4abfa751535cf67609ae,
title = "Phosphorylation of MUC1 by met modulates interaction with p53 and MMP1 expression",
abstract = "MUC1, a transmembrane mucin, is a key modulator of several signaling pathways that affect oncogenesis, motility, and cell morphology. The interaction of MUC1 cytoplasmic tail (MUC1CT) with signal transducers and its nuclear translocation and subsequent biological responses are believed to be regulated by phosphorylation status, but the precise mechanisms by which this occurs remain poorly defined. We detected a novel association between the Met receptor tyrosine kinase and the MUC1CT. Met catalyzed phosphorylation of tyrosine at YHPM in the MUC1CT. Stimulation of S2-013.MUC1F pancreatic cancer cells with hepatocyte growth factor facilitated nuclear localization of MUC1CT, as determined by real time confocal imaging analysis. MUC1 overexpression also facilitated faster turnover of Met. Phosphorylation of MUC1CT by Met enhanced its interaction with p53, which led to suppression of AP1 transcription factor activity through interactions at the MMP1 promoter, ultimately leading to reduced transcription of MMP1. This correlated with a decrease in hepatocyte growth factor-induced invasiveness when MUC1 was overexpressed. The results demonstrate that MUC1 modulates Met-mediated oncogenic signaling in cancer.",
author = "Pankaj Singh and Behrens, {Michelle E.} and Eggers, {John P.} and Ronald Cerny and Bailey, {Jennifer M.} and Kandavel Shanmugam and Gendler, {Sandra J.} and Bennett, {Eric P.} and Hollingsworth, {Michael A}",
year = "2008",
month = "10",
day = "3",
doi = "10.1074/jbc.M805036200",
language = "English (US)",
volume = "283",
pages = "26985--26995",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "40",

}

TY - JOUR

T1 - Phosphorylation of MUC1 by met modulates interaction with p53 and MMP1 expression

AU - Singh, Pankaj

AU - Behrens, Michelle E.

AU - Eggers, John P.

AU - Cerny, Ronald

AU - Bailey, Jennifer M.

AU - Shanmugam, Kandavel

AU - Gendler, Sandra J.

AU - Bennett, Eric P.

AU - Hollingsworth, Michael A

PY - 2008/10/3

Y1 - 2008/10/3

N2 - MUC1, a transmembrane mucin, is a key modulator of several signaling pathways that affect oncogenesis, motility, and cell morphology. The interaction of MUC1 cytoplasmic tail (MUC1CT) with signal transducers and its nuclear translocation and subsequent biological responses are believed to be regulated by phosphorylation status, but the precise mechanisms by which this occurs remain poorly defined. We detected a novel association between the Met receptor tyrosine kinase and the MUC1CT. Met catalyzed phosphorylation of tyrosine at YHPM in the MUC1CT. Stimulation of S2-013.MUC1F pancreatic cancer cells with hepatocyte growth factor facilitated nuclear localization of MUC1CT, as determined by real time confocal imaging analysis. MUC1 overexpression also facilitated faster turnover of Met. Phosphorylation of MUC1CT by Met enhanced its interaction with p53, which led to suppression of AP1 transcription factor activity through interactions at the MMP1 promoter, ultimately leading to reduced transcription of MMP1. This correlated with a decrease in hepatocyte growth factor-induced invasiveness when MUC1 was overexpressed. The results demonstrate that MUC1 modulates Met-mediated oncogenic signaling in cancer.

AB - MUC1, a transmembrane mucin, is a key modulator of several signaling pathways that affect oncogenesis, motility, and cell morphology. The interaction of MUC1 cytoplasmic tail (MUC1CT) with signal transducers and its nuclear translocation and subsequent biological responses are believed to be regulated by phosphorylation status, but the precise mechanisms by which this occurs remain poorly defined. We detected a novel association between the Met receptor tyrosine kinase and the MUC1CT. Met catalyzed phosphorylation of tyrosine at YHPM in the MUC1CT. Stimulation of S2-013.MUC1F pancreatic cancer cells with hepatocyte growth factor facilitated nuclear localization of MUC1CT, as determined by real time confocal imaging analysis. MUC1 overexpression also facilitated faster turnover of Met. Phosphorylation of MUC1CT by Met enhanced its interaction with p53, which led to suppression of AP1 transcription factor activity through interactions at the MMP1 promoter, ultimately leading to reduced transcription of MMP1. This correlated with a decrease in hepatocyte growth factor-induced invasiveness when MUC1 was overexpressed. The results demonstrate that MUC1 modulates Met-mediated oncogenic signaling in cancer.

UR - http://www.scopus.com/inward/record.url?scp=55249096950&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=55249096950&partnerID=8YFLogxK

U2 - 10.1074/jbc.M805036200

DO - 10.1074/jbc.M805036200

M3 - Article

C2 - 18625714

AN - SCOPUS:55249096950

VL - 283

SP - 26985

EP - 26995

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 40

ER -