aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability

• DOI: 10.1038/s41467-018-07739-0
• Publication Date: 2018-12-11T17:47:11Z
• Authors: Meghan Riddell; Akiko Nakayama; Takao Hikita; Fatemeh Mirzapour...; Takuji Kawamura; Ayesha Pasha; Mengnan Li; Mikio Masuzawa; Mario Looso; Tim Steinbacher; Klaus Ebnet; Michael Potente; Tomonori Hirose; Shigeo Ohno; Ingrid Fleming; Stefan Gattenlöhner; Phyu P. Aung; Thuy Phung; Osamu Yamasaki; Teruki Yanagi; Hiroshi Umemura; Masanori Nakayama
• Keywords: FOXO1

Strict regulation of proliferation is vital for development, whereas unregulated cell a fundamental characteristic cancer. The polarity protein atypical kinase C lambda/iota (aPKCλ) associated with through unknown mechanisms. In endothelial cells, suppression aPKCλ impairs despite hyperactivated mitogenic signaling. Here we show that phosphorylates the DNA binding domain forkhead box O1 (FoxO1) transcription factor, gatekeeper growth. Although signaling excludes FoxO1 from nucleus, consequently increasing c-Myc abundance and proliferation, controls expression via FoxO1/miR-34c without affecting its localization. We find this pathway strongly activated in malignant vascular sarcoma, angiosarcoma, aPKC inhibition reduces angiosarcoma cells. Moreover, phosphorylation at Ser218 correlates poor patient prognosis. Our findings may provide potential therapeutic strategy treatment cancers, like angiosarcoma.