AKT

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Akt1, also known as "Akt" or protein kinase B (PKB) is an important molecule in mammalian cellular signaling.

In humans, there are three genes in the "Akt family": Akt1, Akt2, and Akt3. These enzymes are members of the serine/threonine-specific protein kinase family (EC 2.7.11.1).

Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes. Akt1 is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types of cancer. Akt (now also called Akt1) was originally identified as the oncogene in the transforming retrovirus, AKT8.

Akt2 is an important signaling molecule in the Insulin signaling pathway. It's required to induce glucose transport.

These separate roles for Akt1 and Akt2 were demonstrated by studying mice in which either the Akt1 or the Akt2 gene was deleted, or "knocked out". In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a diabetic phenotype (insulin resistance), again consistent with the idea that Akt2 is more specific for the insulin receptor signaling pathway [1].

The role of Akt3 is less clear, though it appears to be predominantly expressed in brain. It has been reported that mice lacking Akt3 have small brains [2].

Contents

[edit] Regulation

Akt possesses a protein domain known as a PH domain, or Pleckstrin Homology domain, named after Pleckstrin, the protein in which it was first discovered. This domain binds to phosphoinositides with high affinity. In the case of the PH domain of Akt, it binds either phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5)P3 aka PIP3) or phosphatidylinositol (3,4)-bisphosphate (PtdIns(3,4)P2 aka PI(3,4)P2). This is useful for control of cellular signaling because the di-phosphorylated phosphoinositide PtdIns(4,5)P2 is only phosphorylated by the family of enzymes, PI 3-kinases (phosphoinositide 3-kinase or PI3K), and only upon receipt of chemical messengers which tell the cell to begin the growth process. For example, PI 3-kinases may be activated by a G protein coupled receptor or receptor tyrosine kinase such as the insulin receptor. Once activated, PI 3-kinases phosphorylates PtdIns(4,5)P2 to form PtdIns(3,4,5)P3, allowing Akt, and its activating kinases, phosphoinositide dependent kinases 1 and 2 (PDK1 and PDK2), to become localized to the membrane where the PDKs and Akt come into contact with one another. Upon contact, PDKs phosphorylate Akt on a serine and a threonine residue, resulting in its activation. Activated Akt can now go on to activate or deactivate its myriad substrates via its kinase activity. See this link for a more thorough and detailed image of the Akt signaling pathway.

Besides being a downstream effector of PI 3-kinases, Akt may also be activated in a PI 3-kinase-independent manner. Studies have suggested that cAMP-elevating agents could activate Akt through protein kinase A (PKA), although these studies are disputed and the mechanism of action is unclear.

The PI3K dependent Akt activation could be regulated through the tumor suppressor PTEN, which works essentially as the opposite of PI3K mentioned above (PTEN and PI3K). PTEN acts as a phosphatase to dephosphorylate PtdIns(3,4,5)P3 back to PtdIns(4,5)P2. This removes the membrane-localization factor from the Akt signaling pathway. Without this localization, the rate of Akt activation decreases significantly, as do the all the downstream pathways that depend on Akt for activation.

[edit] Functions

Akt regulate the cellular survival [3] and metabolism by binding and regulating many downstream effectors, e.g. Nuclear Factor-κB, Bcl-2 family proteins and murine double minute 2 (MDM2).

[edit] Cell survival

Akt could promote growth factor-mediated cell survival both directly and indirectly. BAD is a pro-apoptotic protein of the Bcl-2 family. Akt could phosphorylate BAD on Ser136 (BAD phosphorylation by Akt), which makes BAD dissociate from the Bcl-2/Bcl-X complex and lose the pro-apoptotic function (BAD interaction with Bcl-2). Akt could also activate NF-κB via regulating IκB kinase (IKK), thus result in transcription of pro-survival genes ("NF-kB"+AND+181328[uid&rid=eurekah.figgrp.997 regulation of NF-kB]).

[edit] Metabolism

Akt is required for the insulin-induced translocation of glucose transporter 4 (GLUT4) to the plasma membrane. Glycogen synthase kinase 3 (GSK-3) could be inhibited upon phosphorylation by Akt, which results in promotion of glycogen synthesis. It's worthy to note that GSK3 is also involved in Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway.

[edit] References

  1. ↑ Robert S. Garofalo, Stephen J. Orena, Kristina Rafidi, Anthony J. Torchia, Jeffrey L. Stock, Audrey L. Hildebrandt, Timothy Coskran, Shawn C. Black, Dominique J. Brees, Joan R. Wicks, John D. McNeish, and Kevin G. Coleman (2003) "Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKB beta" Journal of Clinical Investigation Volume 112, pages 197-208. full text online Entrez PubMed 12843127
  2. ↑  Z. Z. Yang, O. Tschopp, A. Baudry, B. Dummler, D. Hynx and B. A. Hemmings. (2004) Physiological functions of protein kinase B/Akt. Biochem Soc Trans. 32:350-354. Review. full text online Entrez PubMed 15046607
  3. ↑  Gang Song, Gaoliang Ouyang and Shideng Bao. (2005) The activation of Akt/PKB signaling pathway and cell survival. J. Cell. Mol. Med. 9:59-71. Download full text (PDF format).

[edit] External links

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