Stephen Jones
IMGENEX India Pvt Ltd. the only biotech company in Orissa and one of its kinds in Eastern India. IMGENEX India started in Oct as an outsourcing branch of IMGENEX Corporation, San Diego, USA.
Akt family of
serine/threonine-directed kinases regulates a diverse array of
biological processes, including cellular survival, proliferation,
glucose homeostasis, and vascular tone and are important molecules in mammalian cellular
signaling. The three widely expressed isoforms of PKB (PKB
, PKBß and PKB
; also known as
Akt1, Akt2 and Akt3, respectively) are each composed of an
N-terminal PtdIns(3,4,5)P3- and PtdIns(3,4)P2-binding
PH domain and a C-terminal kinase catalytic domain. Stimulation by
numerous growth factors, cytokines, hormones and neurotransmitters can activate
PKB/Akt in a phosphoinositide 3-kinase-dependent manner. Through receptor
tyrosine kinases, these stimuli cause phosphoinositide 3-kinase activation, and
generation of the membrane phospholipid PtdIns(3,4,5)P3. PtdIns(3,4,5)P3
then recruits PKB/Akt to the membrane, where it becomes phosphorylated (for PKBa/Akt1)
by upstream kinases,
phosphoinositide-dependent kinase 1. Following
the activation of PI
3-kinase, PKB isoforms are recruited from
the cytosol to the plasma
membrane through their interaction
with PtdIns(3,4,5)
P3
and/or PtdIns(3,4)
P2 where they are thought
to
undergo a conformational change and become activated by phosphorylation
of
two residues. PKB can promote cell survival by inhibiting proteins that mediate
apoptosis. Phosphorylation of BAD
by PKB (and other AGC kinases)
enables it to interact with 14-3-3
proteins, which prevents it from
binding to Bcl-X
L and thereby
suppresses apoptosis. It
directly phosphorylate and inhibit the caspase proteasesm, key executioners of
apoptosis.
PKBbeta, an essential gene
for the maintenance of normal glucose homeostasis and is likely to
represent a critical intermediate
in the insulin signal transduction
pathway. PKB
activation might inhibit apoptosis by promoting the
increased
expression of survival molecules or the degradation of
pro-apoptotic molecules. PKB also phosphorylates and activates endothelial
nitric oxide
synthase, thereby promoting angiogenesis (formation of
new blood
vessels). Inhibition of GSK3 following its phosphorylation
by PKB has
also been suggested to play a role in inhibiting
apoptosis in
neuronal cells. Thus it plays a key role in cancer
progression by stimulating cell
proliferation and inhibiting
apoptosis, which suggests it, likely to be a hot drug target for the treatment
of cancer, diabetes and stroke.
