Threonine 209 phosphorylation on RUNX3 by Pak1 is a molecular switch for its dualistic functions

A. Kumar, M. Singhal, C. Chopra, S. Srinivasan, R. P. Surabhi, R. Kanumuri, S. Tentu, S. Jagadeeshan, S. Sundaram, K. Ramanathan, R. Shankar Pitani, B. Muthuswamy, S. Abhijit, A. S. Nair, G. Venkatraman, S. K. Rayala

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

P21 Activated Kinase 1 (Pak1), an oncogenic serine/threonine kinase, is known to have a significant role in the regulation of cytoskeleton and cellular morphology. Runx3 was initially known for its role in tumor suppressor function, but recent studies have reported the oncogenic role of Runx3 in various cancers. However, the mechanism that controls the paradoxical functions of Runx3 still remains unclear. In this study, we show that Runx3 is a physiologically interacting substrate of Pak1. We identified the site of phosphorylation in Runx3 as Threonine 209 by mass spectrometry analysis and site-directed mutagenesis, and further confirmed the same with a site-specific antibody. Results from our functional studies showed that Threonine 209 phosphorylation in Runx3 alters its subcellular localization by protein mislocalization from the nucleus to the cytoplasm and subsequently converses its biological functions. This was further supported by in vivo tumor xenograft studies in nude mouse models which clearly demonstrated that PANC-28 cells transfected with the Runx3-T209E clone showed high tumorigenic potential as compared with other clones. Our results from clinical samples also suggest that Threonine 209 phosphorylation by Pak1 could be a potential therapeutic target and of great clinical relevance with implications for Runx3 inactivation in cancer cells where Runx3 is known to be oncogenic. The findings presented in this study provide evidence of Runx3-Threonine 209 phosphorylation as a molecular switch in dictating the tissue-specific dualistic functions of Runx3 for the first time.

Original languageEnglish
Pages (from-to)4857-4865
Number of pages9
JournalOncogene
Volume35
Issue number37
DOIs
StatePublished - 15 Sep 2016
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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