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Aberrant cytoplasmic localization of ARID1B activates ERK signaling and promotes oncogenesis

Authors :
Viswakalyan Kotapalli
Satish Rao
Swarnalata Gowrishankar
Padmavathi Kavadipula
Srinivas Animireddy
Murali D. Bashyam
Source :
Journal of Cell Science.
Publication Year :
2020
Publisher :
The Company of Biologists, 2020.

Abstract

The ARID1B/BAF250b subunit of the human SWI/SNF chromatin remodeling complex is a canonical nuclear tumor suppressor. We employed in silico prediction, intracellular fluorescence and cellular fractionation based subcellular localization analyses to identify the ARID1B nuclear localization signal. A cytoplasm-restricted ARID1B-NLS mutant was significantly compromised in its canonical transcription activation and tumor suppressive functions, as expected. Surprisingly however, cytoplasmic localization appeared to induce a gain of oncogenic function in ARID1B as evidenced from several cell line and mouse xenograft based assays. Mechanistically, cytoplasm-localized ARID1B could bind c-RAF and PPP1CA causing stimulation of RAF-ERK signaling and β-catenin transcription activity. ARID1B harboring NLS mutations derived from tumor samples also exhibited aberrant cytoplasmic localization and acquired a neo-morphic oncogenic function via activation of RAF-ERK signaling. Further, immunohistochemistry on a tissue microarray revealed significant correlation of ARID1B cytoplasmic localization with increased levels of active forms of ERK1/2 and β-catenin as well as with advanced tumor stage and lymph node positivity in human primary pancreatic tumor tissues. ARID1B therefore promotes oncogenesis through cytoplasm-based gain of function mechanisms in addition to dysregulation in the nucleus.

Details

ISSN :
14779137 and 00219533
Database :
OpenAIRE
Journal :
Journal of Cell Science
Accession number :
edsair.doi.dedup.....6f4a2367e1988eb3b408d65f27ac9f60