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 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.
Baruch
A
A
Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv, Israel.
Hartmann
M
M
Yoeli
M
M
Adereth
Y
Y
Greenstein
S
S
Stadler
Y
Y
Skornik
Y
Y
Zaretsky
J
J
Smorodinsky
N I
NI
Keydar
I
I
Wreschner
D H
DH
D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics*; D002352:Carrier Proteins / Q000032:analysis*; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018396:Mucin-1 / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000032:analysis*
D002352:Carrier Proteins; D018396:Mucin-1; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C085661:mucin receptor