AKT1

Function

The serine-threonine protein kinase AKT1 is catalytically inactive in serum-starved primary and immortalized fibroblasts. AKT1 and the related AKT2 are activated by platelet-derived growth factor. The activation is rapid and specific, and it is abrogated by mutations in the pleckstrin homology domain of AKT1. It was shown that the activation occurs through phosphatidylinositol 3-kinase. In the developing nervous system AKT is a critical mediator of growth factor-induced neuronal survival. Survival factors can suppress apoptosis in a transcription-independent manner by activating the serine/threonine kinase AKT1, which then phosphorylates and inactivates components of the apoptotic machinery. Mice lacking Akt1 display a 25% reduction in body mass, indicating that Akt1 is critical for transmitting growth-promoting signals, most likely via the IGF1 receptor. Mice lacking Akt1 are also resistant to cancer: They experience considerable delay in tumor growth initiated by the large T antigen or the Neu oncogene. A single-nucleotide polymorphism in this gene causes Proteus syndrome.

History

AKT (now also called AKT1) was originally identified as the oncogene in the transforming retrovirus, AKT8. AKT8 was isolated from a spontaneous thymoma cell line derived from AKR mice by cocultivation with an indicator mink cell line. The transforming cellular sequences, v-akt, were cloned from a transformed mink cell clone and these sequences were used to identify Akt1 and Akt2 in a human clone library. AKT8 was isolated by Stephen Staal in the laboratory of Wallace P. Rowe; he subsequently cloned v-akt and human AKT1 and AKT2 while on staff at the Johns Hopkins Oncology Center.

In 2011, a mutation in AKT1 was strongly associated with Proteus syndrome, the disease that probably affected the Elephant Man.

The name Akt stands for Ak strain transforming. The origins of the Akt name date back to 1928, when J. Furth performed experimental studies on mice that developed spontaneous thymic lymphomas. Mice from three different stocks were studied, and the stocks were designated A, R, and S. Stock A was noted to yield many cancers, and inbred families were subsequently designated by a second small letter (Aa, Ab, Ac, etc.), and thus came the Ak strain of mice. Further inbreeding was undertaken with Ak mice at the Rockefeller Institute in 1936, leading to the designation of the AKR mouse strain. In 1977, a transforming retrovirus was isolated from the AKR mouse. This virus was named Akt-8, the "t" representing its transforming capabilities.

Interactions

AKT1 has been shown to interact with:

• AKTIP,
• BRAF,
• BRCA1,
• C-Raf,
• CDKN1B,
• CHUK
• GAB2,
• HSP90AA1,
• ILK,
• KRT10,
• MAP2K4,
• MAP3K11,
• MAP3K8,
• MAPK14,
• MAPKAPK2,
• MARK2,
• MTCP1,
• MTOR,
• NPM1,
• NR4A1,
• NR3C4,
• PKN2,
• PRKCQ,
• PDPK1,
• PLXNA1,
• TCL1A,
• TRIB3,
• TSC1,
• TSC2, and
• YWHAZ.

References

References

1. "Entrez Gene: AKT1 v-akt murine thymoma viral oncogene homolog 1".
2. (2011). "A mosaic activating mutation in AKT1 associated with the Proteus syndrome". N. Engl. J. Med..
3. Cohen MM. (2014). "Proteus syndrome review: molecular, clinical, and pathologic features". Clin. Genet..
4. (July 1977). "Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma". Proc. Natl. Acad. Sci. U.S.A..
5. Staal SP. (July 1987). "Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma". Proc. Natl. Acad. Sci. U.S.A..
6. (27 July 2011). "A Mosaic Activating Mutation in Associated with the Proteus Syndrome". New England Journal of Medicine.
7. (Feb 2004). "Regulation of apoptosis by the Ft1 protein, a new modulator of protein kinase B/Akt". Mol. Cell. Biol..
8. (Sep 2000). "Negative regulation of the serine/threonine kinase B-Raf by Akt". J. Biol. Chem..
9. (Nov 1999). "Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells". J. Biol. Chem..
10. (Dec 2008). "Negative Regulation of AKT Activation by BRCA1". Cancer Res..
11. (Nov 1999). "Phosphorylation and regulation of Raf by Akt (protein kinase B)". Science.
12. (Aug 2002). "Akt-dependent phosphorylation of p27Kip1 promotes binding to 14-3-3 and cytoplasmic localization". J. Biol. Chem..
13. (Sep 1999). "NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase". Nature.
14. (Sep 1999). "NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling". Nature.
15. (Jan 2002). "PKB-mediated negative feedback tightly regulates mitogenic signalling via Gab2". EMBO J..
16. (Feb 2003). "Regulation of telomerase activity and anti-apoptotic function by protein-protein interaction and phosphorylation". FEBS Lett..
17. (May 2005). "IL-2 increases human telomerase reverse transcriptase activity transcriptionally and posttranslationally through phosphatidylinositol 3'-kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells". J. Immunol..
18. (Sep 2000). "Modulation of Akt kinase activity by binding to Hsp90". Proc. Natl. Acad. Sci. U.S.A..
19. (Sep 1998). "Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase". Proc. Natl. Acad. Sci. U.S.A..
20. (Nov 2001). "Inhibition of protein kinase B (PKB) and PKCzeta mediates keratin K10-induced cell cycle arrest". Mol. Cell. Biol..
21. (Jan 2002). "Akt (protein kinase B) negatively regulates SEK1 by means of protein phosphorylation". J. Biol. Chem..
22. (Feb 2003). "Negative regulation of mixed lineage kinase 3 by protein kinase B/AKT leads to cell survival". J. Biol. Chem..
23. (Aug 2002). "Akt-dependent phosphorylation specifically regulates Cot induction of NF-kappa B-dependent transcription". Mol. Cell. Biol..
24. (Feb 2001). "p38 Kinase-dependent MAPKAPK-2 activation functions as 3-phosphoinositide-dependent kinase-2 for Akt in human neutrophils". J. Biol. Chem..
25. (Mar 2008). "Akt and CHIP coregulate tau degradation through coordinated interactions". Proc. Natl. Acad. Sci. U.S.A..
26. (Feb 2002). "Differential regulation of Akt kinase isoforms by the members of the TCL1 oncogene family". J. Biol. Chem..
27. (Aug 2000). "The protooncogene TCL1 is an Akt kinase coactivator". Mol. Cell.
28. (Feb 2005). "Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex". Science.
29. (Jul 2000). "A direct linkage between the phosphoinositide 3-kinase-AKT signaling pathway and the mammalian target of rapamycin in mitogen-stimulated and transformed cells". Cancer Res..
30. (Apr 2004). "Thr2446 is a novel mammalian target of rapamycin (mTOR) phosphorylation site regulated by nutrient status". J. Biol. Chem..
31. (Oct 2008). "Nuclear Akt interacts with B23/NPM and protects it from proteolytic cleavage, enhancing cell survival". Proc. Natl. Acad. Sci. U.S.A..
32. (Mar 2001). "Akt phosphorylates and regulates the orphan nuclear receptor Nur77". Proc. Natl. Acad. Sci. U.S.A..
33. (Jun 2001). "Akt suppresses androgen-induced apoptosis by phosphorylating and inhibiting androgen receptor". Proc. Natl. Acad. Sci. U.S.A..
34. (Nov 2000). "Inhibition of Akt and its anti-apoptotic activities by tumor necrosis factor-induced protein kinase C-related kinase 2 (PRK2) cleavage". J. Biol. Chem..
35. (Aug 2001). "Complex formation and cooperation of protein kinase C theta and Akt1/protein kinase B alpha in the NF-kappa B transactivation cascade in Jurkat T cells". J. Biol. Chem..
36. (Apr 2002). "Protein kinase B is regulated in platelets by the collagen receptor glycoprotein VI". J. Biol. Chem..
37. (Jul 2001). "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and amino acids arginine 211 and serine 343". J. Biol. Chem..
38. (Aug 2004). "The activity of the plexin-A1 receptor is regulated by Rac". J. Biol. Chem..
39. (May 2002). "A modeled hydrophobic domain on the TCL1 oncoprotein mediates association with AKT at the cytoplasmic membrane". Biochemistry.
40. (Jun 2003). "TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver". Science.
41. (Sep 2004). "Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase". Proc. Natl. Acad. Sci. U.S.A..
42. (Jun 2002). "Identification of 14-3-3zeta as a protein kinase B/Akt substrate". J. Biol. Chem..