Muc4/MUC4 functions and regulation in cancer

Abstract

The membrane mucin MUC4 (human) is abundantly expressed in many epithelia, where it is proposed to play a protective role, and is overexpressed in some epithelial tumors. Studies on the rat homologue, Muc4, indicate that it acts through anti-adhesive or signaling mechanisms. In particular, Muc4/MUC4 can serve as a ligand/modulator of the receptor tyrosine kinase ErbB2, regulating its phosphorylation and the phosphorylation of its partner ErbB3, with or without the involvement of the ErbB3 ligand neuregulin. Muc4/MUC4 can also modulate cell apoptosis via multiple mechanisms, both ErbB2 dependent and independent. Muc4/MUC4 expression is regulated by multiple mechanisms, ranging from transcriptional to post-translational. The roles of MUC4 in tumors suggest that it may be valuable as a tumor marker or target for therapy.

Figure 1. Conformational model for the role of Muc4/MUC4 in ErbB2 and ErbB3 modulation

Muc4/MUC4 (A) binds ErbB2 and can activate phosphorylation of the tyrosines of the tail of an ErbB2–ErbB3 complex (red circles, [B]) in the absence of the ErbB3 ligand neuregulin. The neuregulin is required for the phosphorylation of the ErbB3 (C) and full downstream signaling effects from the ErbB2–ErbB3 complex. The major extracellular domains of the ErbB2 are numbered 1–4 N-terminal to C-terminal. C: C-terminal region of kinase domain of ErbB2 and ErbB3; L: Ligand for ErbB3, neuregulin; N: N-terminal region of kinase domain of ErbB2 and ErbB3.

Figure 2. Muc4/MUC4 contribution to segregation of ErbB2 and ErbB3 in polarized epithelial cells

Muc4/MUC4 interacts with ErbB2 soon after the two are synthesized in the cells and facilitates trafficking of the ErbB2 to the apical surface, where it is effectively segregated from ErbB3, still at the lateral surface, (A) vs (B). Loss of polarity, as in damaged epithelia or tumor cells, breaks the segregation barrier and allows the formation of the ErbB2–ErbB3 complex (C), which is a key element of downstream signaling. Cells that do not contain Muc4/MUC4 have ErbB2 localized to their lateral surfaces along with the ErbB3 (A). Whether they are associated is unclear, but they are not phosphorylated and do not participate in signaling from the lateral surface.