The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3

Melanie Funes, Jamie K. Miller, Cary Lai, Kermit L Carraway, Colleen A Sweeney

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Mucins provide a protective barrier for epithelial surfaces, and their overexpression in tumors has been implicated in malignancy. We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1β (NRG1β) growth factor. In the present study we demonstrate that Muc4 expression in A375 human melanoma cells, as well as MCF7 and T47D human breast cancer cells, enhances NRG1β signaling through the phosphatidylinositol 3-kinase pathway. In examining the mechanism underlying Muc4-potetiated ErbB2 signaling, we found that Muc4 expression markedly augments NRG1β binding to A375 cells without altering the total quantity of receptors expressed by the cells. Cell-surface protein biotinylation experiments and immunofluorescence studies suggest that Muc4 induces the relocalization of the ErbB2 and ErbB3 receptors from intracellular compartments to the plasma membrane. Moreover, Muc4 interferes with the accumulation of surface receptors within internal compartments following NRG1β treatment by suppressing the efficiency of receptor internalization. These observations suggest that transmembrane mucins can modulate receptor tyrosine kinase signaling by influencing receptor localization and trafficking and contribute to our understanding of the mechanisms by which mucins contribute to tumor growth and progression.

Original languageEnglish (US)
Pages (from-to)19310-19319
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number28
DOIs
StatePublished - Jul 14 2006

Fingerprint

Neuregulins
Neuregulin-1
Mucins
Tumors
Receptor Protein-Tyrosine Kinases
Population
Neoplasms
Phosphatidylinositol 3-Kinase
Biotinylation
Phosphorylation
Cell membranes
Growth
Fluorescent Antibody Technique
Melanoma
Intercellular Signaling Peptides and Proteins
Membrane Proteins
Cells
Cell Membrane
Breast Neoplasms
Neoplasm Metastasis

ASJC Scopus subject areas

  • Biochemistry

Cite this

The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3. / Funes, Melanie; Miller, Jamie K.; Lai, Cary; Carraway, Kermit L; Sweeney, Colleen A.

In: Journal of Biological Chemistry, Vol. 281, No. 28, 14.07.2006, p. 19310-19319.

Research output: Contribution to journalArticle

@article{06690fe4e4854261a56ef80403925e34,
title = "The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3",
abstract = "Mucins provide a protective barrier for epithelial surfaces, and their overexpression in tumors has been implicated in malignancy. We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1β (NRG1β) growth factor. In the present study we demonstrate that Muc4 expression in A375 human melanoma cells, as well as MCF7 and T47D human breast cancer cells, enhances NRG1β signaling through the phosphatidylinositol 3-kinase pathway. In examining the mechanism underlying Muc4-potetiated ErbB2 signaling, we found that Muc4 expression markedly augments NRG1β binding to A375 cells without altering the total quantity of receptors expressed by the cells. Cell-surface protein biotinylation experiments and immunofluorescence studies suggest that Muc4 induces the relocalization of the ErbB2 and ErbB3 receptors from intracellular compartments to the plasma membrane. Moreover, Muc4 interferes with the accumulation of surface receptors within internal compartments following NRG1β treatment by suppressing the efficiency of receptor internalization. These observations suggest that transmembrane mucins can modulate receptor tyrosine kinase signaling by influencing receptor localization and trafficking and contribute to our understanding of the mechanisms by which mucins contribute to tumor growth and progression.",
author = "Melanie Funes and Miller, {Jamie K.} and Cary Lai and Carraway, {Kermit L} and Sweeney, {Colleen A}",
year = "2006",
month = "7",
day = "14",
doi = "10.1074/jbc.M603225200",
language = "English (US)",
volume = "281",
pages = "19310--19319",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "28",

}

TY - JOUR

T1 - The mucin Muc4 potentiates neuregulin signaling by increasing the cell-surface populations of ErbB2 and ErbB3

AU - Funes, Melanie

AU - Miller, Jamie K.

AU - Lai, Cary

AU - Carraway, Kermit L

AU - Sweeney, Colleen A

PY - 2006/7/14

Y1 - 2006/7/14

N2 - Mucins provide a protective barrier for epithelial surfaces, and their overexpression in tumors has been implicated in malignancy. We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1β (NRG1β) growth factor. In the present study we demonstrate that Muc4 expression in A375 human melanoma cells, as well as MCF7 and T47D human breast cancer cells, enhances NRG1β signaling through the phosphatidylinositol 3-kinase pathway. In examining the mechanism underlying Muc4-potetiated ErbB2 signaling, we found that Muc4 expression markedly augments NRG1β binding to A375 cells without altering the total quantity of receptors expressed by the cells. Cell-surface protein biotinylation experiments and immunofluorescence studies suggest that Muc4 induces the relocalization of the ErbB2 and ErbB3 receptors from intracellular compartments to the plasma membrane. Moreover, Muc4 interferes with the accumulation of surface receptors within internal compartments following NRG1β treatment by suppressing the efficiency of receptor internalization. These observations suggest that transmembrane mucins can modulate receptor tyrosine kinase signaling by influencing receptor localization and trafficking and contribute to our understanding of the mechanisms by which mucins contribute to tumor growth and progression.

AB - Mucins provide a protective barrier for epithelial surfaces, and their overexpression in tumors has been implicated in malignancy. We have previously demonstrated that Muc4, a transmembrane mucin that promotes tumor growth and metastasis, physically interacts with the ErbB2 receptor tyrosine kinase and augments receptor tyrosine phosphorylation in response to the neuregulin-1β (NRG1β) growth factor. In the present study we demonstrate that Muc4 expression in A375 human melanoma cells, as well as MCF7 and T47D human breast cancer cells, enhances NRG1β signaling through the phosphatidylinositol 3-kinase pathway. In examining the mechanism underlying Muc4-potetiated ErbB2 signaling, we found that Muc4 expression markedly augments NRG1β binding to A375 cells without altering the total quantity of receptors expressed by the cells. Cell-surface protein biotinylation experiments and immunofluorescence studies suggest that Muc4 induces the relocalization of the ErbB2 and ErbB3 receptors from intracellular compartments to the plasma membrane. Moreover, Muc4 interferes with the accumulation of surface receptors within internal compartments following NRG1β treatment by suppressing the efficiency of receptor internalization. These observations suggest that transmembrane mucins can modulate receptor tyrosine kinase signaling by influencing receptor localization and trafficking and contribute to our understanding of the mechanisms by which mucins contribute to tumor growth and progression.

UR - http://www.scopus.com/inward/record.url?scp=33745830104&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33745830104&partnerID=8YFLogxK

U2 - 10.1074/jbc.M603225200

DO - 10.1074/jbc.M603225200

M3 - Article

C2 - 16690615

AN - SCOPUS:33745830104

VL - 281

SP - 19310

EP - 19319

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 28

ER -