Protein kinase B/AKT phosphorylates hypoxia-inducible factor-3α1 in response to insulin, promoting cell growth and migration.

Hypoxia-inducible factors (HIFs) are best known for their roles in the adaptation to low oxygen environments. Besides hypoxia, HIF-1/2 α-subunits are also regulated by various non-hypoxic stimuli including insulin which can act via the PI3K/protein kinase B (PKB) signaling pathway. However, with respect to insulin little is known about HIF-3α. We aimed to investigate this relationship and found that insulin stimulates HIF-3α expression under both normal and low oxygen conditions. Blocking PKB activity reversed the effects of insulin, indicating that HIF-3α is a direct target of PKB. We identified serine 524, located in the oxygen-dependent degradation domain of HIF-3α, as a phosphorylation site of PKB. Mutating serine 524 impaired binding of PKB to HIF-3α and its ubiquitination, suggesting that PKB regulates HIF-3α stability through phosphorylation, thereby affecting important cellular processes such as cell viability and cell adhesion. Importantly, we discovered that this phosphorylation site also influenced insulin-dependent cell migration. These findings shed light on a novel mechanism by which insulin affects PKB-dependent HIF-3α expression and activity, with potential implications in metabolic diseases and cancer.

Defect-Mediated Alloying of Monolayer Transition-Metal Dichalcogenides.

Alloying plays a central role in tailoring the material properties of 2D transition-metal dichalcogenides (TMDs). However, despite widespread reports, the details of the alloying mechanism in 2D TMDs have remained largely unknown and are yet to be further explored. Here, we combine a set of systematic experiments with ab initio density functional theory (DFT) calculations to unravel a defect-mediated mechanism for the alloying of monolayer TMD crystals. In our alloying approach, a monolayer MoSe2 film serves as a host crystal in which exchanging selenium (Se) atoms with sulfur (S) atoms yields a MoS2 xSe2(1- x) alloy. Our study reveals that the driving force required for the alloying of CVD-grown films with abundant vacancy-type defects is significantly lower than that required for the alloying of exfoliated films with fewer vacancies. Indeed, we show that pre-existing Se vacancies in the host MoSe2 lattice mediate the replacement of chalcogen atoms and facilitate the synthesis of MoS2 xSe2(1- x) alloys. Our DFT calculations suggest that S atoms can bind to Se vacancies and then diffuse throughout the host MoSe2 lattice via exchanging the position with Se vacancies, further supporting our proposed defect-mediated alloying mechanism. Beside native vacancy defects, we show that the existence of large-scale defects in CVD-grown MoSe2 films causes the fracture of alloys under the alloying-induced strain, while no such effect is observed in exfoliated MoSe2 films. Our study provides a deep insight into the details of the alloying mechanism and enables the synthesis of 2D alloys with tunable properties.