SUMMARY Transcriptional control requires epigenetic changes directed by mitochondrial tricarboxylic acid (TCA) cycle metabolites. In the mouse embryo, global epigenetic changes occur during the zygotic genome activation (ZGA) at a 2-cell stage. Pyruvate is essential for development beyond this stage, which is at odds with the low activity of mitochondria in this period. We now show that a number of enzymatically active mitochondrial enzymes associated with the TCA cycle essential for epigenetic remodeling are transiently and partially localized to the nucleus. Pyruvate is essential for this nuclear localization, and a failure of TCA cycle enzymes to enter the nucleus correlates with loss of specific histone modifications and a block in ZGA. At later stages, however, these enzymes are exclusively mitochondrial. In humans, the enzyme pyruvate dehydrogenase is transiently nuclear at the 4/8-cell stage coincident with timing of human embryonic genome activation, suggesting a conserved metabolic control mechanism underlying early pre-implantation development.

Background: Substrates of the Hippo pathway kinases Lats1/2 are largely unknown besides YAP/TAZ. Results: Phosphorylation of angiomotin by Lats1/2 inhibits interaction with F-actin thus impairs cell migration and angiogenesis. Conclusion: AMOTp130 is a physiological and functional substrate of Lats1/2 and the Hippo pathway. Significance: Demonstrating how identification of novel substrates would facilitate understanding the physiology of the Hippo pathway.

Highlights d TE formation in mouse embryos is controlled by glucose metabolism activating CDX2 d Glycolysis is dispensable, and glucose is not required for amino acid or lipid synthesis d Nucleotides synthesized from glucose, along with S1P, activate mTOR and TFAP2C d Glucose metabolism by the HBP controls YAP1, which, together with TFAP2C, activates CDX2

PI3K/AKT signaling is known to regulate cancer metabolism, but whether metabolic feedback regulates the PI3K/AKT pathway is unclear. Here, we demonstrate the important reciprocal crosstalk between the PI3K/AKT signal and pentose phosphate pathway (PPP) branching metabolic pathways. PI3K/AKT activation stabilizes G6PD, the rate-limiting enzyme of the PPP, by inhibiting the newly identified E3 ligase TIRM21 and promotes the PPP. PPP metabolites, in turn, reinforce AKT activation and further promote cancer metabolic reprogramming by blocking the expression of the AKT inhibitor PHLDA3. Knockout of TRIM21 or PHLDA3 promotes crosstalk and cell proliferation. Importantly, PTEN null human cancer cells and in vivo murine models are sensitive to anti-PPP treatments, suggesting the importance of the PPP in maintaining AKT activation even in the presence of a constitutively activated PI3K pathway. Our study suggests that blockade of this reciprocal crosstalk mechanism may have a therapeutic benefit for cancers with PTEN loss or PI3K/AKT activation.