TYROSINE PHOSPHORYLATION OF THE MUC1 BREAST-CANCER MEMBRANE-PROTEINS CYTOKINE RECEPTOR-LIKE MOLECULES

Phosphorylation on tyrosine residues is a key step in signal transduct ion pathways mediated by membrane proteins. Although ii is known that human breast cancer tissue expresses at least 2 MUC1 type 1 membrane p roteins (a polymorphic high molecular weight MUC1 glycoprotein that co ntains a variable number of tandem 20 amino acid repeat units, and the MUC1/Y protein that is not polymorphic and is lacking this repeat arr ay) their function in the development of human breast cancer has remai ned elusive. Here it is shown that these MUC1 proteins are extensively phosphorylated, that phosphorylation occurs primarily on tyrosine res idues and that following phosphorylation the MUC1 proteins may potenti ally interact with SH2 domain-containing proteins and thereby initiate a signal transduction cascade. As with cytokine receptors, the MUC1 p roteins do not harbor intrinsic tyrosine kinase activity yet are tyros ine phosphorylated and the MUC1/Y protein participates in a cell surfa ce heteromeric complex whose formation is mediated by two cytoplasmica lly located MUC1 cysteine residues. Furthermore, the MUC1/Y protein de monstrates sequence similarity with sequences present in cytokine rece ptors that are known to be involved in ligand binding. Our results dem onstrate that the two MUC1 isoforms are both likely to function in sig nal transduction pathways and to be intimately linked to the oncogenet ic process and suggest that the MUC1/Y protein may act in a similar fa shion to cytokine receptors.