DF3/MUC1 signaling in multiple myeloma cells is regulated by interleukin-7.
The human DF3/MUC1 transmembrane protein is aberrantly expressed in multiple myeloma cells and other B cell malignancies. The regulation of MUC1 in B cells and its potential function as a signaling molecule are unknown. The present results demonstrate that interleukin-7 (IL-7) stimulates MUC1 expression in multiple myeloma cells. The results also demonstrate the IL-7 induces binding of MUC1 to the Lyn tyrosine kinase. The MUC1 C-terminal subunit binds directly to Lyn through interactions with the Lyn SH3 and SH2 domains. Activation of Lyn in response to IL-7 stimulation results in increased tyrosine phosphorylation of the MUC1 C-terminal subunit. In vitro and in vivo studies show that Lyn phosphorylates MUC1, at least in large part, on a YEKV site in the MUC1 cytoplasmic tail. The functional significance of the MUC1-Lyn interaction is supported by the demonstration that Lyn-mediated phosphorylation of MUC1 on YEKV induces binding of MUC1 and the beta-catenin signaling protein. In concert with these results, IL-7 treatment is associated with binding of MUC1 to beta-catenin and targeting of the MUC1-beta-catenin complex to the nucleus. These findings indicate that IL-7 regulates MUC1 expression and function in multiple myeloma cells.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Yongqing
Y
Li
Wen
W
Chen
Jian
J
Ren
Wei-Hsuan
WH
Yu
Quan
Q
Li
Kiyotsugu
K
Yoshida
Donald
D
Kufe
D000595:Amino Acid Sequence; D003598:Cytoskeletal Proteins / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D015851:Interleukin-7 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000096:biosynthesis*; D009101:Multiple Myeloma / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D011485:Protein Binding; D011994:Recombinant Proteins; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014443:Tyrosine / Q000378:metabolism; D051176:beta Catenin; D019061:src-Family Kinases / Q000378:metabolism
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D015851:Interleukin-7; D018396:Mucin-1; D011994:Recombinant Proteins; D015534:Trans-Activators; D051176:beta Catenin; D014443:Tyrosine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases