Growth factor signaling coupled to activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway plays a crucial role in the regulation of cell proliferation and survival. The key regulatory kinase of Akt has been identified as mammalian target of rapamycin complex 2 (mTORC2), which functions as the PI3K-dependent Ser-473 kinase of Akt. This kinase complex is assembled by mTOR and its essential components rictor, Sin1 and mLST8. The recent genetic screening study in Caenorhabditis elegans has linked a specific point mutation of rictor to an elevated storage of fatty acids that resembles the rictor deficiency phenotype. In our study, we show that in mammalian cells the analogous single rictor point mutation (G934E) prevents the binding of rictor to Sin1 and the assembly of mTORC2, but this mutation does not interfere with the binding of the rictor-interacting protein Protor. A substitution of the rictor Gly-934 residue to a charged amino acid prevents formation of the rictor/Sin1 heterodimer. The cells expressing the rictor G934E mutant remain deficient in the mTORC2 signaling, as detected by the reduced phosphorylation of Akt on Ser-473 and a low cell proliferation rate. Thus, although a full length of rictor is required to interact with its binding partner Sin1, a single amino acid of rictor Gly-934 controls its interaction with Sin1 and assembly of mTORC2.
Mammals have evolved a variety of morphological adaptations that have allowed them to compete in their natural environments. The developmental genetic basis of this morphological diversity remains largely unknown. Bats are mammals that have the unique ability of powered flight. We have examined the molecular embryology of bats and investigated the developmental genetic basis for their highly derived limbs used for flight. Initially, we developed an embryo staging system for a model chiropteran, Carollia perspicillata, the short-tailed fruit bat that has subsequently been used for staging other bat species. Expression studies focusing on genes that regulate limb development indicate that there are similarities and differences between bats and mice. To determine the consequences of these expression differences, we have conducted an enhancer switch assay by gene targeting in mouse embryonic stem cells to create mice whose genes are regulated by bat sequences. Our studies indicate that cis-regulatory elements contribute to the morphological differences that have evolved among mammalian species.
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