TGFbeta regulation of membrane mucin Muc4 via proteosome degradation.
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 TGFbeta, 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 TGFbeta inhibition of Muc4 expression. These results suggest a model in which TGFbeta 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.
Lomako
Wieslawa M
WM
Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine, Florida 33136, USA.
Lomako
Joseph
J
Soto
Pedro
P
Carraway
Coralie A Carothers
CA
Carraway
Kermit L
KL
D000818:Animals; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism; D055264:Mucin-4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D016212:Transforming Growth Factor beta / Q000502:physiology*; D054875:Ubiquitination
D006023:Glycoproteins; D018832:Molecular Chaperones; D055264:Mucin-4; D011498:Protein Precursors; D016212:Transforming Growth Factor beta; D046988:Proteasome Endopeptidase Complex