AKT-induced PKM2 phosphorylation signals for IGF-1-stimulated cancer cell growth

// Young Soo Park 1, 5 , Dong Joon Kim 2 , Han Koo 2, 5 , Se Hwan Jang 3 , Yeon-Mi You 1, 5 , Jung Hee Cho 2 , Suk-Jin Yang 1 , Eun Sil Yu 4 , Yuri Jung 2 , Dong Chul Lee 1 , Jung-Ae Kim 2, 5 , Zee-Yong Park 3 , Kyung Chan Park 2 , Young Il Yeom 1, 5 1 Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141, Korea 2 Personalized Genomic Medicine Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), Daejeon 34141, Korea 3 School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 61005, Korea 4 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea 5 Department of Functional Genomics, University of Science and Technology, Daejeon 34113, Korea Correspondence to: Kyung Chan Park, email: kpark@kribb.re.kr Young Il Yeom, email: yeomyi@kribb.re.kr Zee-Yong Park, email: zeeyong@gist.ac.kr Keywords: PKM2, AKT, IGF-1, phosphorylation of PKM2, STAT5 Received: September 30, 2015     Accepted: June 04, 2016     Published: June 20, 2016 ABSTRACT Pyruvate kinase muscle type 2 (PKM2) exhibits post-translational modifications in response to various signals from the tumor microenvironment. Insulin-like growth factor 1 (IGF-1) is a crucial signal in the tumor microenvironment that promotes cell growth and survival in many human cancers. Herein, we report that AKT directly interacts with PKM2 and phosphorylates it at Ser-202, which is essential for the nuclear translocation of PKM2 protein under stimulation of IGF-1. In the nucleus, PKM2 binds to STAT5A and induces IGF-1-stimulated cyclin D1 expression, suggesting that PKM2 acts as an important factor inducing STAT5A activation under IGF-1 signaling. Concordantly, overexpression of STAT5A in cells deficient in PKM2 expression failed to restore IGF-induced growth, whereas reconstitution of PKM2 in PKM2 knockdown cells restored the IGF-induced growth capacity. Our findings suggest a novel role of PKM2 in promoting the growth of cancers with dysregulated IGF/phosphoinositide 3-kinase/AKT signaling.