Patient derived mutation W257G of PPP2R1A enhances cancer cell migration through SRC-JNK-c-Jun pathway.
Mutation of PPP2R1A has been observed at high frequency in endometrial serous carcinomas but at low frequency in ovarian clear cell carcinoma. However, the biological role of mutation of PPP2R1A in ovarian and endometrial cancer progression remains unclear. In this study, we found that PPP2R1A expression is elevated in high-grade primary tumor patients with papillary serous tumors of the ovary. To determine whether increased levels or mutation of PPP2R1A might contribute to cancer progression, the effects of overexpression or mutation of PPP2R1A on cell proliferation, migration, and PP2A phosphatase activity were investigated using ovarian and endometrial cancer cell lines. Among the mutations, PPP2R1A-W257G enhanced cell migration in vitro through activating SRC-JNK-c-Jun pathway. Overexpression of wild type (WT) PPP2R1A increased its binding ability with B56 regulatory subunits, whereas PPP2R1A-mutations lost the ability to bind to most B56 subunits except B56δ. Total PP2A activity and PPP2R1A-associated PP2Ac activity were significantly increased in cells overexpressing PPP2R1A-WT. In addition, overexpression of PPP2R1A-WT increased cell proliferation in vitro and tumor growth in vivo.
Department of Biological Sciences, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
Ae Lee
AL
Jeong
Department of Biological Sciences, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
Sora
S
Han
Department of Biological Sciences, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
Sunyi
S
Lee
Department of Biological Sciences, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
Jeong
J
Su Park
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Yiling
Y
Lu
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Shuangxing
S
Yu
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jane
J
Li
Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
Kyung-Hee
KH
Chun
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Gordon B
GB
Mills
Department of Biological Sciences, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
Young
Y
Yang
D049109:Cell Proliferation; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*
C517191:PPP2R1A protein, human; D016755:Proto-Oncogene Proteins c-jun; D016392:Proto-Oncogene Proteins pp60(c-src); D054648:Protein Phosphatase 2