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

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 do main and is a cell membrane protein that undergoes transphosphorylation on both serine and tyrosine residues. We have identified cognate binding prote ins that specifically interact with the extracellular domain of MUC/Y. Coim munoprecipitation analyses clearly revealed the presence of complexes compo sed of MUC1/Y and its cognate binding proteins in primary breast tumor tiss ue. 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 a lso derived from the MUC1 gene and represent the secreted mucin-like polymo rphic MUC1 proteins MUC1/SEC and MUC1/REP, which contain tandem repeat arra y, 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 MUC/Y. The interaction of MUC1/Y wit h MUC1/SEC has important biological functional correlates: (at it induces M UC1/Y phosphorylation; and (b) it has a pronounced effect on cell morpholog y, These findings suggest that MUC1/Y and MUC1/SEC form an active receptor/ cognate binding protein complex that can elicit cellular responses. The pro teins comprising this complex are, thus, generated by alternative splicing from one and the same gene, namely the MUC1 gene.