Characterization of the MUC1-C Cytoplasmic Domain as a Cancer Target.
Mucin 1 (MUC1) is a heterodimeric protein that is aberrantly expressed in diverse human carcinomas and certain hematologic malignancies. The oncogenic MUC1 transmembrane C-terminal subunit (MUC1-C) functions in part by transducing growth and survival signals from cell surface receptors. However, little is known about the structure of the MUC1-C cytoplasmic domain as a potential drug target. Using methods for structural predictions, our results indicate that a highly conserved CQCRRK sequence, which is adjacent to the cell membrane, forms a small pocket that exposes the two cysteine residues for forming disulfide bonds. By contrast, the remainder of the MUC1-C cytoplasmic domain has no apparent structure, consistent with an intrinsically disordered protein. Our studies thus focused on targeting the MUC1 CQCRRK region. The results show that L- and D-amino acid CQCRRK-containing peptides bind directly to the CQC motif. We further show that the D-amino acid peptide, designated GO-203, blocks homodimerization of the MUC1-C cytoplasmic domain in vitro and in transfected cells. Moreover, GO-203 binds directly to endogenous MUC1-C in breast and lung cancer cells. Colocalization studies further demonstrate that GO-203 predominantly binds to MUC1-C at the cell membrane. These findings support the further development of agents that target the MUC1-C cytoplasmic domain CQC motif and thereby MUC1-C function in cancer cells.
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, United States of America; Genus Oncology, Boston, MA, 02118, United States of America.
Deepak
D
Raina
LeadInvent, New Delhi, India.
Praveen
P
Agarwal
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, United States of America.
James
J
Lee
Boston University School of Medicine, Department of Medicine, Boston, MA, 02118, United States of America.
Ajit
A
Bharti
Boston University School of Medicine, Department of Physiology & Biophysics, Boston, MA, 02118, United States of America.
C James
CJ
McKnight
LeadInvent, New Delhi, India.
Pankaj
P
Sharma
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, United States of America; Genus Oncology, Boston, MA, 02118, United States of America.
Surender
S
Kharbanda
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, United States of America.
Donald
D
Kufe
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D021381:Protein Transport
C060192:MUC1 protein, human; D018396:Mucin-1