Expression of sialomucin complex/Muc -4, an intramembrane ligand of ErbB2, in the female reproductive tract and its regulation in the uteru

SMC is composed of a highly O-glycosylated mucin subunit ASGP-1 noncovalently attached to the membrane via a transmembrane subunit ASGP-2, which contains two EGF-like sequences. SMC was recently identified to be homologous to human MUC4. SMC/Muc4 is abundantly expressed at the luminal apical surface of most tissues of the female reproductive tract where it is hypothesized to have multiple functions. In the uterine glandular epithelium, oviduct, cervix and vagina, SMC/Muc4 is constitutively expressed and does not change significantly during the estrous cycle. However, at the uterine luminal epithelial surface, SMC/Muc4 expression is regulated by estrogen and progesterone during the estrous cycle, indicating that hormonal regulation of SMC/Muc4 is restricted only to the uterine luminal epithelium.;The mechanism by which SMC/Muc4 is regulated at the uterine luminal epithelium was investigated using hormone-responsive primary cultures of rat uterine luminal epithelial cells (RULECs). These cultured cells express SMC/Muc4 which is not altered by treatments with estrogen or progesterone. SMC/Muc4 is downregulated when RULECs are co-cultured with isolated uterine stromal cells or when RULECs were treated with TGF-beta1. However, estrogen and anti-TGF-beta block the stromal cell effect. These results suggest an indirect hormonal regulation of SMC in RULECs, in which TGF-beta acts as a hormonally-regulated paracrine factor which suppresses SMC production to permit blastocyst implantation in pregnant animals.;Recently our laboratory reported that the ASGP-2 can act as an intramembrane ligand for ErbB2, a receptor for which no soluble ligand has been identified. The presence of ErbB2 has been previously reported in the uterus and vagina, where it decreases in the uterine luminal epithelia during pregnancy in a pattern similar to that of SMC. SMC/Muc4 and ErbB2 are co-expressed and form a complex in different tissues of the female reproductive tract where they may have a potential function in epithelial cell proliferation/differentiation. In addition, these results show that differentially-localized forms of ErbB2 are recognized by different antibodies, raising interesting questions about the mechanism for differential localization and possible functions of ErbB2/SMC association in the female reproductive tract. They also raise a cautionary note about the use of different ErbB2 antibodies for expression and localization studies.