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Platelet-Derived Growth Factor Receptor ß–Mediated Phosphorylation of MUC1 Enhances Invasiveness in Pancreatic Adenocarcinoma Cells

¹ Eppley Institute for Research in Cancer and Allied Diseases and ² Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska; ³ Department of Biochemistry/Molecular Biology Program, Mayo Clinic College of Medicine, Scottsdale, Arizona; ⁴ Schepens Eye Research Institute, Harvard Medical School, Boston, Massachusetts; and ⁵ University of Nebraska-Lincoln, Lincoln, Nebraska

Requests for reprints: Michael A. Hollingsworth, Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 986805 Nebraska Medical Center, Omaha, NE 68198-6805. Phone: 402-559-8343; Fax: 402-559-3339; E-mail: mahollin{at}unmc.edu.

MUC1 is a heterodimeric transmembrane glycoprotein that is overexpressed and aberrantly glycosylated in ductal adenocarcinomas. Differential phosphorylation of the MUC1 cytoplasmic tail (MUC1CT) has been associated with signaling events that influence the proliferation and metastasis of cancer cells. We identified a novel tyrosine phosphorylation site (HGRYVPP) in the MUC1CT by mass spectrometric analysis of MUC1 from human pancreatic adenocarcinoma cell lines. Analyses in vitro and in vivo showed that platelet-derived growth factor receptor ß (PDGFRß) catalyzed phosphorylation of this site and of tyrosine in the RDTYHPM site. Stimulation of S2-013.MUC1F cells with PDGF-BB increased nuclear colocalization of MUC1CT and ß-catenin. PDGF-BB stimulation had no significant effect on cell proliferation rate; however, it enhanced invasion in vitro through Matrigel and in vivo tumor growth and metastases. Invasive properties of the cells were significantly altered on expression of phosphorylation-abrogating or phosphorylation-mimicking mutations at these sites. We propose that interactions of MUC1 and PDGFRß induce signal transduction events that influence the metastatic properties of pancreatic adenocarcinoma. [Cancer Res 2007;67(11):5201–10]

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