Membrane proximal ectodomain cleavage of MUC16 occurs in the acidifying Golgi/post-Golgi compartments

Srustidhar Das, Prabin D. Majhi, Mona H. Al-Mugotir, Satyanarayana Rachagani, Paul L Sorgen, Surinder Kumar Batra

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number9759
JournalScientific reports
Volume5
DOIs
StatePublished - Jun 5 2015

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Membranes
Secretory Pathway
Gene Expression Regulation
Tumor Biomarkers
Ovarian Neoplasms
Chromatin
Epitopes
Amino Acids
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Membrane proximal ectodomain cleavage of MUC16 occurs in the acidifying Golgi/post-Golgi compartments. / Das, Srustidhar; Majhi, Prabin D.; Al-Mugotir, Mona H.; Rachagani, Satyanarayana; Sorgen, Paul L; Batra, Surinder Kumar.

In: Scientific reports, Vol. 5, 9759, 05.06.2015.

Research output: Contribution to journalArticle

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