University of Miami
Kozloski, Goldi Attias.
Muc4 Modulation of Ligand-Independent ErbB2 Signaling.
Degree: PhD, Biochemistry and Molecular Biology (Medicine), 2009, University of Miami
The membrane mucin Muc4 is a heterodimer, bi-functional glycoprotein complex that is normally expressed in epithelial tissue. Functional studies on the extracellular mucin subunit of Muc4 have shown that it acts to promote anti-adhesion properties by sterically interfering with cell-cell and cell-matrix interactions and that the extent of this effect is directly associated with the number of tandem repeats on this subunit. Functional studies on the transmembrane subunit of Muc4 have shown that this subunit participates in intracellular signaling through interaction with the receptor tyrosine kinase ErbB2. This role of Muc4 was shown to be mediated by stabilizing the heregulin ligand-induced ErbB2-ErbB3 heterodimer through interference with the internalization process of these receptors, thus potentiating the PI3K, a survival-signaling pathway that is mediated by this heterodimer. However, Muc4 was also shown to potentiate ErbB2 phosphorylation in the absence of heregulin by an unknown mechanism. The aim of this work was to examine the role of Muc4 in intracellular signaling by evaluating the ligand-independent Muc4-ErbB2 interaction. Biochemical analyses of A375 human melanoma cells expressing Muc4 under different cell treatments, and probed with phospho-specific antibodies, were used to understand the mechanism. An antibody microarray screen was used to decipher the intracellular activated signaling pathways. The results of the mechanistic analysis indicated that Muc4 potentiates ErbB2 signaling significantly by interacting with ErbB2 and ErbB3 and by stabilizing the kinase active ErbB2 receptor, thus increasing its phosphorylation signal half-life and resulting in sustained ErbB2 signaling. The signaling pathway analysis suggests that through Muc4 direct interaction with ErbB2, signaling pathways that promote loss of cell polarity are activated. Loss of cell-cell adhesion is mediated by interference with the cadherin-catenin complex stability, and loss of cell-matrix adhesion is mediated by facilitating focal adhesion turnover. Together, these results suggest that Muc4 is a potent oncogenic factor, and further enhance our understanding of the role that Muc4 plays in ligand-independent intracellular signaling.
Advisors/Committee Members: Richard S. Myers - Committee Chair, Thomas K. Harris - Committee Member, Kermit L. Carraway - Mentor, Lidia Kos - Outside Committee Member.
Subjects/Keywords: Ligand-independent Activity; Microarray Screen; Heregulin; Anti-adhesion; Heterodimer; Phosphorylation; ErbB2 Signaling; Receptor Tyrosine Kinase; Membrane Mucin; Muc4; Epidermal Growth Factor Receptor
to Zotero / EndNote / Reference
APA (6th Edition):
Kozloski, G. A. (2009). Muc4 Modulation of Ligand-Independent ErbB2 Signaling. (Doctoral Dissertation). University of Miami. Retrieved from https://scholarlyrepository.miami.edu/oa_dissertations/253
Chicago Manual of Style (16th Edition):
Kozloski, Goldi Attias. “Muc4 Modulation of Ligand-Independent ErbB2 Signaling.” 2009. Doctoral Dissertation, University of Miami. Accessed August 23, 2019.
MLA Handbook (7th Edition):
Kozloski, Goldi Attias. “Muc4 Modulation of Ligand-Independent ErbB2 Signaling.” 2009. Web. 23 Aug 2019.
Kozloski GA. Muc4 Modulation of Ligand-Independent ErbB2 Signaling. [Internet] [Doctoral dissertation]. University of Miami; 2009. [cited 2019 Aug 23].
Available from: https://scholarlyrepository.miami.edu/oa_dissertations/253.
Council of Science Editors:
Kozloski GA. Muc4 Modulation of Ligand-Independent ErbB2 Signaling. [Doctoral Dissertation]. University of Miami; 2009. Available from: https://scholarlyrepository.miami.edu/oa_dissertations/253