The breast cancer-associated MUC1 gene generates both a receptor and its cognate binding protein

Abstract

MUC1 proteins, some of which contain a mucin-like domain and others lacking this region, can be generated from the human breast cancer-associated MUC1 gene by alternative splicing. The MUC1/Y isoform is devoid of the mucin domain and is a cell membrane protein that undergoes transphosphorylation on both serine and tyrosine residues. We have identified cognate binding proteins that specifically interact with the extracellular domain of MUC1/Y. Coimmunoprecipitation analyses clearly revealed the presence of complexes composed of MUC1/Y and its cognate binding proteins in primary breast tumor tissue. MUC1/Y-expressing mammary tumor cells can be specifically targeted, in vivo, with the labeled cognate binding protein. The k(D) of MUC1/Y for its binding proteins was estimated as 1.2 nM. The MUC1/Y binding proteins are also derived from the MUC1 gene and represent the secreted mucin-like polymorphic MUC1 proteins MUC1/SEC and MUC1/REP, which contain a tandem repeat array. Whereas nonposttranslationally modified MUC1/Y bound efficiently to MUC1/SEC, the latter mucin-like protein had to be posttranslationally modified in a cell-type specific manner to bind MUC1/Y. The interaction of MUC1/Y with MUC1/SEC has important biological functional correlates: (a) it induces MUC1/Y phosphorylation; and (b) it has a pronounced effect on cell morphology. These findings suggest that MUC1/Y and MUC1/SEC form an active receptor/ cognate binding protein complex that can elicit cellular responses. The proteins comprising this complex are, thus, generated by alternative splicing from one and the same gene, namely the MUC1 gene.