Pathology Outlines

Stains
Akt

Authors: Satbir Thakur, Ph.D., Emeka Enwere, Ph.D.

Topic Completed: 1 February 2016

Revised: 8 December 2019

Copyright: 2002-2018, PathologyOutlines.com, Inc.

PubMed Search: Akt [title]

Page views in 2018: 3

Page views in 2019 to date: 12

Table of Contents

Cite this page: Satbir T. Akt. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stainsAKT.html. Accessed December 10th, 2019.

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

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