Platelet-derived growth factor receptor beta-mediated phosphorylation of MUC1 enhances invasiveness in pancreatic adenocarcinoma cells.
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 beta (PDGFRbeta) 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 beta-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 PDGFRbeta induce signal transduction events that influence the metastatic properties of pancreatic adenocarcinoma.
Singh
Pankaj K
PK
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Wen
Yunfei
Y
Swanson
Benjamin J
BJ
Shanmugam
Kandavel
K
Kazlauskas
Andrius
A
Cerny
Ronald L
RL
Gendler
Sandra J
SJ
Hollingsworth
Michael A
MA
D000230:Adenocarcinoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D018396:Mucin-1; D009077:Mucins / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
D000951:Antigens, Neoplasm; C060192:MUC1 protein, human; D018396:Mucin-1; D009077:Mucins; D051176:beta Catenin; D014443:Tyrosine; D020797:Receptor, Platelet-Derived Growth Factor beta