Akt Pathway (Very Basic)

Note: Akt = PKB = Protein kinase B

Presence of a primary messenger, such as a growth factor or ligand, causes dimerization of receptor protein-tyrosine kinase (RTKs), or proteins with both receptors and protein kinases. The two individual RTKs cross phosphorylate each other’s cytosolic C-terminus tails. Phosphorylation causes the interaction with downstream elements such as PI 3-kinase, which interact with the phosphorylated regions on the RTKs. Such interactions activates PI-3 kinase, which then phosphorylates PIP2 and change it to PIP3. Next, Akt (a serine/threonine kinase) binds to PIP3 (PIP3 is a secondary messenger) via a pleckstrin homology (PH) domain. After such formation, two other units, an mTORC2 unit and a PDK-1 unit (PDK-1 itself is also bound to a PIP3) come in to phosphorylate the Akt. Now Akt is activated and can allow for the phosphorylation and activation of other molecules.

One pathway Akt can affect is the NF-kB protein, which normally has its nuclear localization signal (NLS) hidden from importins by an IkB protein. However, Akt can activate IkB kinase, which then phosphorylates IkB for ubiquitination. Thus, NF-kB’s NLS is now exposed to importins, which can guide it into the nucleus and allow for transcription of pro-survival genes.

Another method Akt can control survival is via interaction with FOXO, which is used to transcribe genes for cell destruction if allowed to enter nucleus. However, phosphorylation of FOXO allows for binding of a 14-3-3 protein to the former, thus sequestering the FOXO from entering the nucleus and causing transcription. By doing so, Akt’s activation, in presence of growth factors, allow for cell proliferation through repression of FOXO.

Akt also affects various eukaryotic initiation factors, such as eIF2 (with tRNA which holds methionine) through indirect interaction with another section of the translation process. Akt inactivates a GSK-3, which phosphorylates eIF2B, a protein necessary for recharging GTP back onto eIF2. Normally eIF2B would exchange the GDP (spent) on eIF2 for a fresh GTP, which allows for further initiation of translation. However, when there is a lack of growth factors, GSK-3 phosphorylates the eIF2B, preventing the exchange of GTP and preventing translation. However, in presence of growth factors, the activation of Akt will phosphorylate GSK-3, which prevents it from inhibiting eIF2B and thus allows normal translation and cell proliferation to continue.

Likewise, Akt also affects the mTOR1 pathway. Activation of Akt also activates mTOR1, which now can phosphorylate the 4E-BP (4E binding protein). The 4E-BP normally binds to eIF4E on the 5’ end of the messenger RNA. eIF4E is an initiation factor necessary for initiation of translation. However, the 4E-BP inhibits it and prevents such translation from occurring. However, in presence of growth factors, activation of Akt, thus the activation of mTOR1, will phosphorylate the 4E-BP. 4E-BP thus falls off and allows for activation of eIF4E and binding of other initiation factors, therefore, allowing translation and cell proliferation to occur.