Activation of WNT3A prevents deactivation of Nrf2 by GSK3b

Highlights

Activation of WNT3A prevents deactivation of Nrf2 by GSK3b.

Post

After reading some amount of studies about PI3K / Akt / GSK3 / Nrf2, I came to conclusion (or suspicion) that sluggish Nrf2 activation as a health problem is not just “Nrf2” issue.

It seems that there is a balance between constant activation and constant inhibition which should smoothly respond to changing state of the cell.

But for some reason way too many people end up with a state where Nrf2 inactivation is stronger than activation - this is where people start to eat SFN, MSM, and polyphenols to activate Nrf2 manually. It works to some degree, but the root cause is not addressed.

There is an obvious evil-player here - GSK3b. It’s normally active in the resting state of the cell and it downregulates Nrf2 activation. It has many inhibitors that will allow Nrf2 activation (e.g. lithium).

But also the upstream pathways that inhibit GSK3b are responsible for the shift in the balance - we should explore them to see which nutrients / stressors are affecting them.

One quick candidate is Wnt pathway, which also talks to ERK, which is related to Strontium status. I have a feeling that there are some minerals that we don’t appreciate yet, that play the role of amplifiers (like Chromium) or direct controller (like Lithium) of GSK3b or Akt.

Something must be missing or in excess that disrupts the balance of active activation and inhibition of GSK3b.

Reference paper

WNT-3A activates NRF2 in a β-Catenin- and KEAP1-independent manner.

WNT-3A stabilized NRF2 by preventing its GSK-3-dependent phosphorylation and subsequent SCF/β-TrCP-dependent ubiquitination and proteasomal degradation.

Axin1 and NRF2 were physically associated in a protein complex that was regulated by WNT-3A, involving the central region of Axin1 and the Neh4/Neh5 domains of NRF2.

Axin1 knockdown increased NRF2 protein levels, while Axin1 stabilization with Tankyrase inhibitors blocked WNT/NRF2 signaling. (R1)