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

Oncogene
A KumarS K Rayala

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 c...Continue Reading

References

May 25, 2004·Oncogene·Suk-Chul Bae, Joong-Kook Choi
May 26, 2006·Nature Reviews. Cancer·Rakesh KumarChristopher J Barnes
Jun 13, 2009·PloS One·Takaaki TsunematsuTakashi Takata
Jan 27, 2011·Journal of Cellular Biochemistry·Yasusei KudoTakashi Takata
May 27, 2011·Gynecologic Oncology·Cecilia Wei Lin LeeYoshiaki Ito
Nov 28, 2012·International Journal of Cancer. Journal International Du Cancer·Linda Shyue Huey ChuangYoshiaki Ito

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Citations

Jun 20, 2017·Small GTPases·Arun KumarGanesh Venkatraman
Feb 13, 2018·BMB Reports·Sarala Manandhar, You Mie Lee
Sep 19, 2020·Cancer Cell International·Asad Ur RehmanSyed Akhtar Husain

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