Stains
Akt

Author: Thakur Stabir Singh, Ph.D. (see Authors page)
Editor: Emeka Enwere, Ph.D.

Revised: 24 February 2016, last major update February 2016

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: Akt [title]

Cite this page: Akt. PathologyOutlines.com website. http://pathologyoutlines.com/topic/stainsakt.html. Accessed October 19th, 2017.
Definition / general
  • The Akt family is comprised of 3 closely related serine / threonine protein kinases (Akt1, Akt2 and Akt3), which regulate many processes including metabolism, proliferation, cell survival, growth, inhibition of apoptosis and angiogenesis
  • These kinases phosphorylate serine or threonine residues on a range of downstream substrates
  • They are activated by various factors such as insulin, PI3K, IGF1
  • Akt was named after a cell transforming retrovirus isolated from a spontaneous thymoma in AKR mice (Proc Natl Acad Sci U S A 1987;84:5034)
  • Due to its involvement in various cellular processes that promote cell survival and growth, the AKT pathway is a major target for cancer drug discovery
Terminology
  • "Akt" usually refers to Akt1
  • AKT1 is also called RAC-alpha serine / threonine protein kinase, v-akt murine thymoma viral oncogene homolog 1, and protein kinase B (PKB), and is encoded by the AKT1 gene
Pathophysiology
  • Akt regulates glucose uptake by mediating insulin induced translocation of the glucose transporter to the cell surface
  • Akt plays a role as a key modulator of the AKT-mTOR signaling pathway, which controls a variety of cellular processes including new neuron integration during adult neurogenesis, correct neuron positioning, dendritic development and synapse formation (Protein Data Bank)
  • The protein activity of Akt is stimulated by phosphorylation at 2 regulatory sites, Thr308 and Ser473 (OMIM - 164730)
  • Akt is normally expressed in the cytoplasm, nucleus and cell membrane; upon activation it translocates to the nucleus (Abcam)
  • Clinical features
    • Akt is associated with tumor cell survival, proliferation and invasiveness
    • The activation of Akt is one of the most frequent alterations observed in human cancer and tumor cells
    • Tumor cells that have constantly active Akt may depend on Akt for survival, so understanding Akt and its pathways is important
    • A mosaic activating mutation (c. 49G→A, p.Glu17Lys) in AKT1 is associated with Proteus Syndrome, which causes overgrowth of skin, connective tissue, brain and other tissues (Wikipedia - Protein kinase B)
    • AKT-GSK3B signaling is a target of lithium and has been implicated in the pathogenesis of mood disorders, and has a role in schizophrenia (Nat Genet 2004;36:131)
    • A somatic mutation at amino acid 17 of AKT1, resulting in glutamic acid to lysine substitution, has been observed in human breast, colorectal and ovarian cancers
      • This mutation activates AKT1 and localizes it to the plasma membrane, stimulating downstream signaling, resulting in cell transformation and induction of leukemia in mice (Nature 2007;448:439)
    • Mutations resulting in upregulation of AKT1 phosphorylated at Thr308 have been shown to be involved in Cowden syndrome (Am J Hum Genet 2013;92:76)
    • Dysregulation of the AKT1 pathway may be important in the pathogenesis of intrahepatic cholangiocarcinoma (Mod Pathol 2012;25:131)
    • Akt pathway may induce autophagy in cancer cells (J Biol Chem 2012;287:25325)

    Mice models:
  • A combination of activated Ras and Akt induced high grade gliomas with the histologic features of human glioblastoma after gene transfer to neural progenitors (Nat Genet 2000;25:55)
  • Akt1 null mice are smaller than wild type littermates, and have shorter lifespan upon exposure to genotoxic stress
  • Males have increased spontaneous apoptosis in testes and thymus (Genes Dev 2001;15:2203)
  • In a cardiac specific Akt transgenic mouse model, Akt overexpression produced cardiac hypertrophy at the molecular and histologic levels, with a significant increase in cardiomyocyte cell size and concentric left ventricular hypertrophy
  • Akt transgenic mice also showed a remarkable increase in cardiac contractility compared with wild type (Proc Natl Acad Sci U S A 2002;99:12333)
  • Akt1 / Akt2 double knockout mice showed severe growth deficiency and died shortly after birth
    • These mice displayed impaired skin development due to a proliferation defect, skeletal muscle atrophy due to a marked decrease in individual muscle cell size, and impaired bone development (Genes Dev 2003;17:1352)
  • Akt1 deficient mice showed alterations in the expression of genes in the prefrontal cortex involved in synaptic function, neuronal development, myelination and actin polymerization (Proc Natl Acad Sci U S A 2006;103:16906)
  • Uses by pathologists
    • Pathways involving AKT signaling are upregulated in a variety of cancers
    • Phosphorylation of Akt1 is associated with a poor prognosis in early breast cancer
    • Tumors with high levels of Akt1 have been associated with tamoxifen and doxorubicin resistance, resulting in poor prognostic outcome (J Pathol 2012;227:481)
    Microscopic (histologic) images

    Images hosted on Other server:

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    Various images, testis

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    Various images, breast ductal carcinoma

    Positive staining - normal
    • Uterus, cervix, ovary, testis, lung, liver (adult), lymph node, brain (fetal), peripheral blood mononuclear cells
    Positive staining - disease
    • Most malignancies show moderate to strong nuclear AKT staining
    Negative staining
    • Brain (adult), hair follicle, liver (fetal), bone, colon muscle, nasopharynx, T cells