Aberrant cytoplasmic localization of ARID1B activates ERK signaling and promotes oncogenesis

Author:

Animireddy Srinivas12,Kavadipula Padmavathi13,Kotapalli Viswakalyan13,Gowrishankar Swarnalata4ORCID,Rao Satish3,Bashyam Murali Dharan1ORCID

Affiliation:

1. Laboratory of Molecular Oncology, Centre for DNA Fingerprinting and Diagnostics, Hyderabad 500039, India

2. Graduate studies, Manipal Academy of Higher Education, Manipal 576104, India

3. Krishna Institute of Medical Sciences, Hyderabad 500003, India

4. Apollo Hospitals, Hyderabad 500033, India

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.

Funder

Department of Biotechnology, Ministry of Science and Technology, India

Publisher

The Company of Biologists

Subject

Cell Biology

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