PKB and the Mitochondria: AKTing on Apoptosis

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Updated: Aug 30, 2023
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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, initially discovered through homology cloning, maintained a similar appearance to protein kinase A and C in its kinase domain, and therefore, was named as 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 which is highly expressed in the brain and testis (Hanada, 2004).

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PKB has been shown to be a downstream target of receptor tyrosine kinases and is regulated by various cell stimuli. Given its regulation and response to stimuli, 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), a central kinase domain, and a carboxyl-terminal regulatory domain. This structure is characteristic of AGC due to its hydrophobic motif (Hanada, 2004). In the inactive state of PKB, the PH intramolecularly interacts with the kinase domain. When the kinase domain becomes partially unfolded, the PH will interact with PIP3, allowing PDK1 to phosphorylate the activation loop and unfold PKB, which then exposes the substrate binding site (Marks, 2017).

PKB Signaling Pathways

The pro-mitogenic pathway of PKB inactivates many cell cycle inhibitors, such as p21 and p27, to stimulate cell proliferation. Through insulin signaling, PKB inactivates GSK3 to promote glycogen synthesis and attracts Glut 4 to the membrane. This indirectly activates 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, is on the JNK pathway in neural cells. PKB affects the JIP1 and JNK complex formation, which reduces the cytotoxicity of kainate and can lead to the prevention of apoptosis in 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 the matrix (Franke, 1997). PKB’s importance in the inhibition of apoptosis of neuronal cells through various pathways has led scientists to consider 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 shown promising antitumor effects (Hanada, 2004).

BAD is a member of the 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). The 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 therefore apoptosis. PKB can also phosphorylate and inactivate 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