In Vivo Role of INPP4B in Tumor and Metastasis Suppression through Regulation of PI3K–AKT Signaling at Endosomes

Chen Li Chew, Andrea Lunardi, Federico Gulluni, Daniel T. Ruan, Ming Chen, Leonardo Salmena, Michiya Nishino, Antonella Papa, Christopher Ng, Jacqueline Fung, John G. Clohessy, Junko Sasaki, Takehiko Sasaki, Roderick T. Bronson, Emilio Hirsch, Pier Paolo Pandolfi

The phosphatases PTEN and INPP4B have been proposed to act as tumor suppressors by antagonizing PI3K/AKT signaling, and are frequently dysregulated in human cancer. While PTEN has been extensively studied, little is known about the underlying mechanisms by which INPP4B exerts its tumor suppressive function and its role in tumorigenesis in vivo. Here, we show that a partial or complete loss of Inpp4b morphs benign thyroid adenoma lesions in Pten heterozygous mice into lethal and metastatic follicular-like thyroid cancer (FTC). Importantly, analyses of human thyroid cancer cell lines and specimens reveal INPP4B downregulation in FTC. Mechanistically, we find that INPP4B, but not PTEN, is enriched in the early endosomes of thyroid cancer cells, where it selectively inhibits AKT2 activation and in turn tumor proliferation and anchorage-independent growth. We therefore identify INPP4B as a novel tumor suppressor in FTC oncogenesis and metastasis through localized regulation of PI3K/AKT pathway at the endosomes.