TGFβ regulation of membrane mucin Muc4 via proteosome degradation

Abstract

Muc4 is a heterodimeric membrane mucin implicated in epithelial differentiation and tumor progression. It is expressed from a single gene as a 300 kDa precursor protein which is cleaved in the endoplasmic reticulum to its two subunits. Our previous work has shown that Muc4 is regulated by TGFβ, which represses the precursor cleavage. Working with Muc4-transfected A375 tumor cells, we now show that Muc4 undergoes proteosomal degradation. Proteosome inhibitors prolong the life of the precursor, shunt the Muc4 into cytoplasmic aggresomes, increase the level of Muc4 associated with the endoplasmic reticulum chaperones calnexin and calreticulin and increase the levels of ubiquitinated Muc4. Most importantly, proteosome inhibitors repress the TGFβ inhibition of Muc4 expression. These results suggest a model in which TGFβ inhibits precursor cleavage, shunting the precursor into the proteosomal degradation pathway. Thus, the cells have evolved a mechanism to use the quality control pathway for glycoproteins to control the quantity of the protein produced.

Effects of Thymoquinone in the Expression of Mucin 4 in Pancreatic Cancer Cells: Implications for the Development of Novel Cancer Therapies

“…Interestingly, it has been recently published that the transforming growth factor-β (TGF-β) represses MUC4 expression by proteasomal pathway (40). Similarly, other reports indicate that MUC4 expression is inhibited posttranscriptionally by the TGF-β pathway as well (41, 42).…”

Muc4/MUC4 Functions and Regulation in Cancer

“…These results suggested a role for proteosomal degradation in the regulation of Muc4. Blocking proteosome activity increases levels of Muc4 [62]. This block also increases the level of ubiquitinated Muc4 and of Muc4 associated with calnexin and calreticulum.…”

“…This block also increases the level of ubiquitinated Muc4 and of Muc4 associated with calnexin and calreticulum. Undegraded Muc4 in cells treated with proteosome inhibitors is shunted to aggresomes [62]. Tumor cells do not show a similar downregulation of Muc4 because the tumors have lost their responsiveness to TGFβ [59].…”

Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer

“…During pulmonary disease, neutrophil elastase increases the expression of MUC4, possibly to activate epithelial repair mechanisms [90]. The anti-inflammatory cytokine TGF-β prevents cleavage of the MUC4 SEA domain and directs MUC4 for proteosomal degradation [91]. During inflammatory bowel disease, MUC12 is upregulated by TNF-α and TGF-β [81].…”