PKB and the Mitochondria: AKTing on Apoptosis

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Updated: Feb 27, 2021
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Function and Structure of PKB

PKB contains three isoforms with catalytic domains similar to those in the AGC kinase family. PKB? was initially discovered through homology cloning and the similar appearance of its kinase domain resembled that of protein kinase A and C therefore it was named protein kinase B (PKB). It has two family members PKB?/c-Akt2 (c-Akt is a cellular homologue of PKB) which is expressed mainly in insulin target tissues and PKB?/c-Akt3 highly expressed in brain and testis ( Hanada, 2004). PKB has been shown to be a downstream target of receptor tyrosine kinases and is regulated by the cell stimuli. Due to its regulation and response to things such as growth factors and insulin it plays a critical role in the growth and survival of cells.

The structure of PKB includes an amino terminal pleckstrin homology domain (PH), central kinase domain and carboxyl- terminal regulatory domain which is characteristic of AGC because it is a hydrophobic motif (Hanada, 2004). In the inactive state of PKB the PH intramolecularly interacts with the kinase domain when this becomes partially unfolded the PH will interact with PIP3 and thus PDK1 will phosphorylate the activation loop and unfold PKB exposing the substrate binding site (Marks, 2017 ).

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PKB Signaling Pathways

The pro- mitogenic pathway of PKB inactivates many cell cycle inhibitors such as p21 and p27 for stimulation of cell proliferation. Insulin signaling, PKB inactivates GSK3 to promote glycogen synthesis and attracts Glut 4 to the membrane to indirectly activating mTOR for protein synthesis. A third pathway is the anti apoptotic signaling, where PKB inhibits activity from the FOXO transcription factors to stimulate pro- apoptotic genes like Fas Ligand. PKB has two binding sites on the stress mediated MAP- kinase pathway. The first one JIP1, on the JNK pathway in neural cells. PKB affects the JIP1 and JNK complex formation which reduces cytotoxicity of kainate and can lead to the prevention of apoptosis on neural cells (Hanada, 2004).

PKB Regulation of Apoptosis

The regulation of PKB appears to be dependent on the activation of PI3K activity which regulates cell survival. The overexpression of PKB prevents apoptosis in cerebellar neurons induced by the survival factor withdrawal or inhibition of PI3K, as well as the active PKB blocking apoptosis of detached MDCK cells from matrix (Franke, 1997). PKB importance in the inhibition of apoptosis of neuronal cells through various pathways has brought scientists to think of the possibility of using drug therapy to target PKB for neurodegenerative diseases.

Heat shock proteins regulate PKB by binding to PKB. Hsp27-PKB activates and inhibits the apoptosis of neutrophils. In Hsp90, PKB competes with cdc37 for binding but when PKB is dissociated from the complex Hsp90/cdc37 apoptosis may follow. The studies of the Hsp90 inhibitors that degrade PKB have a promising antitumor effects (Hanada, 2004).

BAD is a member of Bcl-2 family when the Ser136 phosphorylates BAD it inhibits its proapoptotic activity on cells. The BAD protein is said to be a direct target of PKB in promoting cell survival (Hanada, 2004). Stress- activated protein kinase (SAPK) pathway is said to be responsible for the promotion of apoptosis. PKB interacts and phosphorylates ASK1 which inhibits the SAPK pathway and therefor apoptosis. PKB can also phosphorylate and the inactivation of MLK3, another MKKK that is upstream of SAPK, and promotes cell survival (Hanada, 2004). PKB seems to be an important part of many apoptosis pathways and can be a clear target for the prevention of apoptosis in cells.

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PKB And The Mitochondria: AKTing On Apoptosis. (2021, Feb 27). Retrieved from