Human embryonic stem cells (hESCs) self-renew indefinitely and give rise to derivatives of all three primary germ layers, yet little is known about the signaling cascades that govern their pluripotent character. Because it plays a prominent role in the early cell fate decisions of embryonic development, we have examined the role of TGFβ superfamily signaling in hESCs. We found that, in undifferentiated cells, the TGFβ/activin/nodal branch is activated (through the signal transducer SMAD2/3) while the BMP/GDF branch(SMAD1/5) is only active in isolated mitotic cells. Upon early differentiation, SMAD2/3 signaling is decreased while SMAD1/5 signaling is activated. We next tested the functional role of TGFβ/activin/nodal signaling in hESCs and found that it is required for the maintenance of markers of the undifferentiated state. We extend these findings to show that SMAD2/3 activation is required downstream of WNT signaling, which we have previously shown to be sufficient to maintain the undifferentiated state of hESCs. Strikingly, we show that in ex vivo mouse blastocyst cultures, SMAD2/3 signaling is also required to maintain the inner cell mass (from which stem cells are derived). These data reveal a crucial role for TGFβ signaling in the earliest stages of cell fate determination and demonstrate an interconnection between TGFβ and WNT signaling in these contexts.

Stat3 activation has been associated with cytokine-induced proliferation, anti-apoptosis, and transformation. Constitutively activated Stat3 has been found in many human tumors as well as v-abl- and v-src-transformed cell lines. Because of these correlations, we examined directly the relationship of activated Stat3 to cellular transformation and found that wild-type Stat3 enhances the transforming potential of v-src while three dominant negative Stat3 mutants inhibit v-srctransformation. Stat3 wild-type or mutant proteins did not affect v-ras transformation. We conclude that Stat3 has a necessary role in v-src transformation.

We report new functions of the cell‐adhesion molecule E‐cadherin in murine pluripotent cells. E‐cadherin is highly expressed in mouse embryonic stem cells, and interference with E‐cadherin causes differentiation. During cellular reprogramming of mouse fibroblasts by OCT4, SOX2, KLF4 and c‐MYC, fully reprogrammed cells were exclusively observed in the E‐cadherin‐positive cell population and could not be obtained in the absence of E‐cadherin. Moreover, reprogrammed cells could be established by viral E‐cadherin in the absence of exogenous OCT4. Thus, reprogramming requires spatial cues that cross‐talk with essential transcription factors. The cell‐adhesion molecule E‐cadherin has important functions in pluripotency and reprogramming. There is a [Hot off the Press][1] (July 2011) associated with this Scientific Report. [1]: http://dx.doi.org/10.1038/embor.2011.117

Hepatocyte nuclear factors 3 α, β, and γ (Foxa-1, -2, and -3) are transcriptional activators of important metabolic genes in the liver that are suppressed by the actions of insulin. Here, we show that the activation of phosphatidylinositol 3-kinase–Akt by insulin induces Foxa-2 phosphorylation, nuclear exclusion, and inhibition of Foxa-2-dependent transcriptional activity. Foxa-2 physically interacts with Akt, a key mediator of the phosphatidylinositol 3-kinase pathway and is phosphorylated at a single conserved site (T156) that is absent in Foxa-1 and Foxa-3 proteins. This Akt phosphorylation site in Foxa-2 is highly conserved from mammals to insects. Mutant Foxa-2 _T156A is resistant to Akt-mediated phosphorylation, nuclear exclusion, and transcriptional inactivation of Foxa-2-regulated gene expression. These results implicate an evolutionarily conserved mechanism in the regulation of Foxa-2-dependent transcriptional control by extracellular signals such as insulin.