PI3K/PTEN-mTORC1 signaling regulate Nedd4-1

PTEN is a lipid phosphatase that converts phosphatidylinositol-3, 4, 5-trisphosphate (PtdInsP3) into phosphatidylinositol-4, 5-bisphosphate (PtdInsP2) and antagonizes phosphoinositide 3-kinase (PI3K)–dependent signaling. Nedd4-1 (neural precursor cell expressed, developmentally down-regulated 4-1) was the first E3 ligase to be implicated in PTEN ubiquitination. Nedd4-1 may catalyze the mono- and polyubiquitination of PTEN, leading to nuclear import of PTEN and PTEN degradation, d thereby regulate axonal growth in neurons.

Previous in vitro and in vivo results show that the Nedd4-family E3 ligases Nedd4-1 and Nedd4-2 play an evolutionarily conserved role in the regulation of axon morphogenesis.

First, we show that PTEN limits Nedd4-1 protein levels by modulating the activity of mTORC1, a protein complex that controls protein synthesis and cell growth.

Next, Nedd4-family E3 ligases Nedd4-1 and Nedd4-2 promote axon growth in mammalian central nervous system neurons. The expression, ubiquitination, localization, or phosphatase activity of PTEN is not changed.

Oppositely, PTEN negatively regulates Nedd4-1 expression at the translational level. And that mammalian Nedd4-1 and Nedd4-2 regulate axon growth.

Our data demonstrate that Nedd4-family E3 ligases promote axonal growth and branching in the developing mammalian brain, wherePten is not a relevant substrate. Instead, PTEN controls neuritis growth by regulating Nedd4-1 expression.

Retinoid homeostasis is critical for normal embryonic development. Key regulatory factors that mediate the pleiotropic effects of RA include several classes of RA-binding transcription factors, the retinoic acid receptors RARa, RARb, and RARg. SIRT1, a nuclear NAD+-dependent protein deacetylase, is the most conserved member of the sirtuin family of enzymes.

Firstly, we show that SIRT1 de?ciency is associated with elevated RA signaling and development defects in mice. We have identi?ed both CRABPI and CRABPII as hyper-acetylated proteins in SIRT1 null mouse embryonic?broblasts (MEFs) in a global stable isotope labeling by amino acids in cell culture (SILAC)-based analysis of Lys acetylation.

Next, we examined whether SIRT1 could physically interact with CRABPs. We analyzed the subcellular localizations of HA-CRABPII in WT and SIRT1 KO MEFs by immuno?uorescent staining CRABPII is a cellular RA carrier that translocates from the cytosol into the nucleus upon RA binding to activate the nuclear RA receptors.

We show that RA-mediated acetylation ofCrabpii at K102 is essential for its nuclear accumulation and subsequent activation of RA signaling. SIRT1 interacts with and deacetylates CRABPII, regulating its subcellular localization.

At last, deletion of SIRT1 leads to increased RA-induced mESC differentiation.

In summary, we have shown that through deacetylation CRABPII, SIRT1 plays a vital role in the regulation of cellular RA signaling and mESC pluripotency. This SIRT1/CRABPII/RAR signaling cascade will provide a way to study gene-environment interactions that affect animal development.

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.