AKT (PROTEIN KINASE B)

Protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate

groups to them (phosphorylation).

Protein kinase B (PKB), also known as Akt, is a serine/threonine-specific protein kinase that

plays a key role in multiple cellular processes such as glucose metabolism, apoptosis, cell

proliferation, transcription and cell migration

TYPES

Akt1-

Involved in cellular survival pathways, by inhibiting apoptotic processes.

Akt1 is also able to induce protein synthesispathways, and is therefore a key signaling

protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general

tissue growth.

Mouse model with complete deletion of Akt1 manifests growth retardation and increased

spontaneous apoptosis in tissues such as testes and thymus. Since it can block apoptosis,

and thereby promote cell survival, Akt1 has been implicated as a major factor in many

types of cancer

Akt2-

It is an important signaling molecule in the insulin signaling pathway. It is required to

induce glucose transport.

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.

Akt3-

The role of Akt3 is less clear, though it appears to be predominantly expressed in the

brain.

It has been reported that mice lacking Akt3 have small brain.

NAME-

The name Akt does not refer to its function. The "Ak" in Akt was a temporary

classification name for a mouse bred and maintained by Jacob Furth that developed

spontaneous thymic lymphomas.

The "t" stands for 'thymoma'; the letter was added when a transforming retrovirus was

isolated from the Ak strain, which was termed "Akt-8". When the oncogene encoded in

this virus was discovered, it was termed v-Akt. Thus, the later identified human

analogues were named accordingly.

SIGNALLING PATHWAY-

The Akt Pathway, or PI3K-Akt Pathway is a signal transduction pathway that promotes

survival and growth in response to extracellular signals. Key proteins involved

arephosphatidylinositol 3-kinase (PI3K) and Akt, or Protein Kinase B

Initial stimulation by a growth factor causes activation of a cell surface receptor

and phosphorylation of PI3K. Activated PI3K then phosphorylates lipids on the plasma

membrane, forming second messenger phosphatidylinositol (3,4,5)-trisphosphate (PIP3).

Akt, a serine/threonine kinase, is recruited to the membrane by interaction with these

phosphoinositide docking sites, so that it can be fully activated. Activated Akt mediates

downstream responses, including cell survival, growth, proliferation, cell migration and

angiogenesis, by phosphorylating a range of intracellular proteins. The pathway is present

in all cells of higher eukaryotes and is highly conserved.

Regulation-

The PI3K-Akt pathway has many downstream effects and must be carefully regulated.

One of the ways the pathway is negatively regulated is by reducing

PIP3 levels. Phosphatase and tensin homolog (PTEN) antagonises PI3K by converting

PI(3,4,5)P3 into PI(4,5)P2. Loss of PTEN function leads to over-activation of Akt and is

common in cancer cells (PTEN is a tumour suppressor).

SH2-containing Inositol Phosphatase (SHIP) also dephosphorylates PI(3,4,5)P3, at the 5'

position of the inositol ring. The PI3K-Akt pathway regulates PTEN levels by affecting

its transcription and activity. When Akt is activated, PTEN is further repressed in

a positive feedback loop.

When the pathway is activated by insulin, insulin receptor substrate 1 (IRS-1)

transcription is down-regulated, in a negative feedback loop via mTORC1 and S6K1

activation.

ROLE IN CANCER-

Aberrant activation of Akt, either via PI3K or independently of PI3K, is often associated with

malignancy. Functional inactivation of PTEN, the major PI3K antagonist, can occur in cancer

cells by point mutation, gene deletion. Mutation in the pathway can also affect receptor tyrosine

kinases, growth factors, Ras and the PI3K p110 subunit, leading to abnormal signalling activity.

Therefore many of the proteins in the pathway are targets for cancer therapeutics. In addition to

its effects on cell survival and cell cycle progression, the PI3K-Akt pathway promotes

other characteristics of cancer cells. Hyperactivity of the pathway promotes the epithelial-

mesenchymal transition (EMT) and metastasis due to its effects on cell migration. This allows

spreading of the primary tumour to other sites and is responsible for 90% of mortalities linked to

cancer.

Angiogenesis

Angiogenesis, the formation of new blood vessels, is often critical for tumour cells to

survive and grow in nutrient-depleted conditions.

Akt is activated downstream of vascular endothelial growth factor (VEGF) in endothelial

cells in the lining of blood vessels, promoting survival and growth.

Akt also contributes to angiogenesis by activatingendothelial nitric oxide

synthase (eNOS), which increases production of nitric oxide (NO). This stimulates

vasodilation and vascular remodeling.

Signalling through the PI3K-Akt pathway increases translation of hypoxia-inducible

factor α (HIF1α and HIF2α) transcription factors. HIF promotes gene expression of

VEGF and glycolytic enzymes, allowing metabolism in oxygen-depleted environments.

Glucose Metabolism

In cancer cells, an increase in Akt signalling correlates with an increase in glucose

metabolism, compared to normal cells. Cancer cells favour glycolysis for energy

production over mitochondrial oxidative phosphorylation, even when oxygen supply is

not limited. This is known as the Warburg effect, or aerobic glycolysis.

Akt affects glucose metabolism by increasing translocation of glucose

transporters GLUT1 and GLUT4 to the plasma membrane,

increasing hexokinase expression and phosphorylating GSK3 which stimulates

glycogen synthesis.

It also activates glycolysis enzymes indirectly, via HIF transcription factors and

phosphorylation of phosphofructokinase-2 (PFK2) which activatesphosphofructokinase-

1 (PFK1).

THERAPEUTIC POTENTIAL-

1) CANCER

Akt is associated with tumour cell survival, proliferation and invasiveness. Activation

of Akt is one of the most frequent alterations observed in human cancer and tumour

cells.

Tumor cells have constantly active Akt and may depend on Akt for survival.

Therefore, understanding Akt and its pathway is important for creation of better

therapies to treat cancer and tumour cells.

2) PROTEUS SYNDROME

A mosaic activating mutation in Akt causes this syndrome.

Overgrowth of skin, connective tissue, brain and other tissues.

Akt INHIBITORS-

PRODUCT NAME INFORMATION PHASE OF CLINICAL TRIAL

ARQ 092 Akt1 inhibitor for Proteus syndrome Phase 0 dose finding trial in Nov 2015

Perifosine (KRX-0401) Novel Akt inhibitor Phase 3

MK-2206 Allosteric Akt inhibitor Phase 2

Ipatasertib (GDC-0068) Highly selective, targets Akt 1/2/3 Phase 2 in 2014

Afuresertib

(GSK2110183)

Potent, orally available Akt inhibitor

for Akt1, Akt2 and Akt3

Phase 2 in 2015

APPROVED Akt INHIBITOR- MILTEFOSINE

Used in the treatment of any form of leishmaniasis

Can be used in the treatment of primary amoebic meningoencephalitis

REFERENCES-

www.wikipedia.com

www.cancer.gov

www.invivogen.com

www.cancernetwork.com

www.myelomabeacon.com

www.pharmaceuticalintelligence.com

www.arqule.com

www.clinicaltrials.gov