This document discusses protein kinase B (Akt), which plays roles in processes like glucose metabolism and cell proliferation. It describes the three main types of Akt (Akt1, Akt2, Akt3) and their physiological functions. Akt1 promotes cell survival and growth, while Akt2 functions in insulin signaling pathways. Akt3's role is less clear. The document outlines Akt's involvement in signaling pathways and its implications for pharmacology. Akt signaling is implicated in cancer development and progression through processes like angiogenesis and glucose metabolism. Several Akt inhibitors are discussed that are in clinical trials for conditions like cancer and Proteus syndrome.

1. BHAGYA SIRIPALLI,
PHARMACOLOGY, SVIPS.
AKT (PROTEIN KINASE B)

2. INTRODUCTION
Protein kinase B (PKB), also known as Akt, is a serine/threonine-specific
protein kinase.
Plays a key role in multiple cellular processes such as
 Glucose metabolism
 Cell proliferation
 Transcription
 Cell migration.

3. TYPES
AKT1 AKT2
AKT3

4. PHYSIOLOGICAL FUNCTIONS

5. AKT1
AKT 1 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.
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.
CELL
SURVIVAL
PATHWAYS

6. AKT2
INSULIN SIGNALING
PATHWAY
SIGNALING
MOLECULE
MOUSE WITH
AKT1,
WITHOUT
AKT2
Akt2 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.
Akt isoforms are overexpressed in a variety of human
tumors, and, at the genomic level, are amplified in gastric
adenocarcinomas (Akt1), ovarian (Akt2), pancreatic (Akt2) and
breast (Akt2) cancer.

7. AKT3
ROLE
LESS
CLEAR
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 brains.

8. NAME
• TEMPORARY CLASSIFICATION
OF MICE WHICH DEVELOPED
THYMIC LYMPHOMAAk
• THYMOMA
t

9. SIGNALING PATHWAYAND PHARMACOLOGICAL
IMPLICATIONS

10. Akt signaling pathway in metabolism, apoptosis,
proliferation
Initial
stimulatio
n by
growth
factor
Activation of
cell surface
receptor &
phosphoryl
ation of PI3K
Phosphor
ylates lipids
on plasma
membran e
Forms 2nd
messenger
PIP3
Akt is
activated
Mediates cell
growth,
survival,
angiogenesis

11. Regulation

12. ROLE IN CANCER

13. 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.

14. Glucose metabolism
 In cancer cells, an increase in Aktsignaling correlates with an
increase in glucose metabolism, compared to normal cells.
 Cancer cells favor glycolysis for energy production over mitochondrial
oxidative phosphorylation, even when oxygen supplyis not limited.
This is known as the Warburg effect, or aerobic glycolysis.

15. Cell survival
Overview of signal transduction pathways involved in apoptosis.
Akt could promote growth factor-mediated cell survival both directly and
indirectly.
Cell cycle
Akt is known to play a role in the cell cycle. Under various circumstances, activation
of Akt was shown to overcome cell cycle arrest in G1 and G2 phases. Moreover,
activated Akt may enable proliferation and survival of cells that have sustained a
potentially mutagenic impact and, therefore, may contribute to acquisition of
mutations in other genes.
Other functions

16. Metabolism
Akt2 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 increase of glycogen
synthesis.
Lysosomal biogenesis and autophagy
Akt regulates TFEB, a master controller of lysosomal biogenesis, by direct
phosphorylation at serine 467. Phosphorylated TFEB is excluded from the nucleus
and less active. Pharmacological inhibition of Akt promotes nuclear translocation
of TFEB, lysosomal biogenesis and autophagy.
Other functions: Cntd

17. THERAPEUTIC POTENTIAL
Clinical relevance
Akt is associated with tumor cell survival, proliferation, and invasiveness.
The activation of Akt is also 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. Therefore, understanding Akt and its pathways is important for the creation
of better therapies to treat cancer and tumor cells.
A mosaic-activating mutation (c. 49G→A, p.Glu17Lys) in AKT1 is associated with the
Proteus Syndrome, which causes overgrowth of skin, connective tissue, brain and other
tissues.

18. 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, targetsAkt
1/2/3
Phase 2 in 2014
Afuresertib
Potent, orally available Akt
inhibitor for Akt1, Akt2and
Phase 2 in 2015

19. APPROVED Akt INHIBITOR
MILTEFOSINE
Any form of leishmaniasis
Can be used in the treatment of primary amoebic
meningoencephalitis.
Ipatasertib is in phase II trials for breast cancer.