Phosphorylation of MUC1 by Met modulates interaction with p53 and MMP1 expression.
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.
Singh
Pankaj K
PK
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Behrens
Michelle E
ME
Eggers
John P
JP
Cerny
Ronald L
RL
Bailey
Jennifer M
JM
Shanmugam
Kandavel
K
Gendler
Sandra J
SJ
Bennett
Eric P
EP
Hollingsworth
Michael A
MA
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects* / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D018396:Mucin-1 / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C066855:HGF protein, human; C060192:MUC1 protein, human; D018396:Mucin-1; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; C495901:TP53 protein, human; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1