In Vivo Role of XXXX in Tumor and Metastasis Suppression through Regulation of PI3K-AKT Signaling at Endosomes.

@entity1 @entity5 @entity19 @entity71815 @entity2370 @entity983 @entity23698 @entity3 @entity652 @entity259 @entity49854
UNASSIGNED: The phosphatases @entity983 and @entity49854 have been proposed to act as @entity5 suppressors by antagonizing PI3K-AKT signaling and are frequently dysregulated in @entity1 @entity5 . Although @entity983 has been extensively studied, little is known about the underlying mechanisms by which @entity49854 exerts its @entity5 -suppressive function and its role in tumorigenesis in vivo. Here, we show that a partial or complete loss of @entity71815 morphs benign thyroid @entity652 in @entity2370 heterozygous @entity19 into lethal and metastatic @entity259 ( @entity259 ). Importantly, analyses of @entity1 @entity259 cell lines and specimens reveal @entity49854 downregulation in @entity259 . Mechanistically, we find that @entity49854 , but not @entity983 , is enriched in the early endosomes of @entity259 cells, where it selectively inhibits @entity23698 activation and in turn @entity5 proliferation and anchorage-independent growth. We therefore identify @entity49854 as a novel @entity5 suppressor in @entity259 oncogenesis and @entity3 through localized regulation of the PI3K-AKT pathway at the endosomes. SIGNIFICANCE: Although both @entity983 and @entity49854 can inhibit PI3K-AKT signaling through their lipid phosphatase activities, here we demonstrate lack of an epistatic relationship between the two @entity5 suppressors. Instead, the qualitative regulation of PI3K- @entity23698 signaling by @entity49854 provides a mechanism for their cooperation in suppressing thyroid tumorigenesis and @entity3 . @entity5 Discov; 5(7); 1-12.   2015 AACR.See related commentary by Vo and Fruman, p. 697.See related article by Kofuji and colleagues, p. 730.
