Muc4 Regulation of Erbb2/erbb3 Signaling

INTRODUCTION. Muc4(SMC) is a cell surface glycoprotein composed of two non-covalently bound subunits: an O-glycosylated mucin subunit, ASGP-1, and a mainly N-glycosylated transmembrane subunit ASGP-2 that anchors the molecule to the plasma membrane. The latter serves as an intramembrane ligand for the receptor tyrosine kinase ErbB2 via an EGF-like domain. This interaction occurs shortly after synthesis of the proteins, and yields a stable complex. The ErbB2 present in the complex appears activated, but it displays a limited state of phosphorylation. The Muc4 ErbB2 complex has been demonstrated on ascites tumors, normal lactating mammary gland, isolated rat mammary epithelial cells, Muc4-transfected MCF-7 breast cancer cells, and insect cells infected via the baculovirus expression system. Muc4 is constutively expressed in many tissues, where it serves mainly a protective function. It is tightly regulated in the mammary gland and the female reproductive tract. In some adenocarcinomas this regulatory mechanism has been repressed, and Muc4 is highly overexpressed. Muc4 and ErbB2 are co-expressed in most accessible and vulnerable epithelia in mammals, and overexpression of both have been seen in cancers of the pancreas, squamous cells, and some breast cancers. In normal epithelia Muc4 is apically localized, while ErbB2 is considered a basolateral protein. However, Muc4 translocates ErbB2 to the apical surface after transfection into polarized CACO-2 cells, where is observed in complex with Muc4. Examination of basolateral proteins, such as sodium/potassium ATPase, indicates that the translocation of ErbB2 is not the result of depolarization of the CACO-2 cells. This change of localization of ErbB2 by Muc4 is a novel mechanism that may be of great relevance, since it positions ErbB2 in a different environment, with different integral membrane proteins, that may allow ErbB2 to initiate different signaling pathways.