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2015 ; 5
(ä): 9759
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Membrane proximal ectodomain cleavage of MUC16 occurs in the acidifying
Golgi/post-Golgi compartments
#MMPMID26044153
Das S
; Majhi PD
; Al-Mugotir MH
; Rachagani S
; Sorgen P
; Batra SK
Sci Rep
2015[Jun]; 5
(ä): 9759
PMID26044153
show ga
MUC16, precursor of the most widely used ovarian cancer biomarker CA125, is up
regulated in multiple malignancies and is associated with poor prognosis. While
the pro-tumorigenic and metastatic roles of MUC16 are ascribed to the
cell-associated carboxyl-terminal MUC16 (MUC16-Cter), the exact biochemical
nature of MUC16 cleavage generating MUC16-Cter has remained unknown. Using
different lengths of dual-epitope (N-terminal FLAG- and C-terminal HA-Tag) tagged
C-terminal MUC16 fragments, we demonstrate that MUC16 cleavage takes place in the
juxta-membrane ectodomain stretch of twelve amino acids that generates a ~17?kDa
cleaved product and is distinct from the predicted sites. This was further
corroborated by domain swapping experiment. Further, the cleavage of MUC16 was
found to take place in the Golgi/post-Golgi compartments and is dependent on the
acidic pH in the secretory pathway. A similar pattern of ~17?kDa cleaved MUC16
was observed in multiple cell types eliminating the possibility of cell type
specific phenomenon. MUC16-Cter translocates to the nucleus in a cleavage
dependent manner and binds to the chromatin suggesting its involvement in
regulation of gene expression. Taken together, we demonstrate for the first time
the oft-predicted cleavage of MUC16 that is critical in designing successful
therapeutic interventions based on MUC16.