Insulin signaling: generic cascades
The binding of Insulin to the extracellular domain of the
Insulin receptor results in the activation of the tyrosine
kinase activity of the receptor. Following the autophosphorylation, the
Insulin receptor phosphorylates a number of intracellular
substrates to initiate a series of intracellular signaling pathways. These substrates
include Insulin receptor substrates-1 and -2
(IRS-1, IRS-2), and SHC (Src
homology 2 domain containing) transforming protein 1
(Shc). The Phosphotyrosine
residues in both IRS-1, IRS-2
and Shc act as docking sites for other
proteins which contain Src-homology 2 (SH2) domains. The two most important are Growth
factor receptor bound 2 (Grb2) and the Phosphatidylinositol
3-kinase, regulatory (PI3K reg class
IA), which lead to the activation of Harvey
rat sarcoma viral oncogene homolog (H-Ras)/
Mitogen-activated protein kinase 1-3 (ERK1/2) and
PI3-kinase pathways, respectively , , .
Son of sevenless homolog (Sos) is a guanine nucleotide
exchange factor (GEF) that promotes the exchange of GDP on Ras with GTP, yielding the
active form of H-Ras. In response to
protein GRB-2 binds to SOS.
GRB-2 - SOS complex is able to binds to phosphorylated
IRS-1, IRS-2 or Shc. This
binding is thought to bring the GRB-2-SOS complex to the
plasma membrane in the vicinity of H-Ras .
Activated H-Ras initiates v-raf-1 murine leukemia viral
oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein
kinase kinases 1 and 2 (MEK1(MAP2K1) MEK2(MAP2K2))/
Mitogen-activated protein kinase 1-3 (ERK1/2) cascade that
results in the stimulation of Ribosomal protein S6 kinase, 90kDa, polypeptide 1
(p90RSK1) , . This signaling
cascade modulates activity of Eukaryotic elongation factor-2 kinase
(eEF2K) via Eukaryotic translation elongation factor 2
(eEF2) activation and regulates translation at the
PI3K is activated when its regulator subunit
PI3K reg class IA becomes bound to IRS-1
or IRS-2, resulting in an increase in the
product PtdIns(3,4,5)P3 , .
The activation of PI3K appears to be necessary for many
of the effects of Insulin, including the protein kinase
cascades involving 3-phosphoinositide dependent protein kinase-1
PDK1(PDPK1), v-akt murine thymoma viral oncogene homolog 1
(AKT(PKB)) and Ribosomal protein S6 kinase, 70kDa,
polypeptides 1 and 2 (p70 S6K1 and p70
S6K2). PtdIns(3,4,5)P3 is able to exert a
dual effect on AKT(PKB) activation involves both direct
binding and activation of AKT(PKB) and stimulation of the
upstream kinase PDK1(PDPK1) and subsequently
phosphorylation and activation of AKT(PKB)
AKT(PKB) is able to phosphorylate Glycogen synthase
kinase 3 beta (GSK3 beta), thereby decreasing
the activity of this kinase. As a consequence, AKT(PKB)
abolishes the inhibition of glycogen synthesis and activates translation
via the regulatory activity of initiation factor of translation Eukaryotic translation
initiation factor 2 (eIF2). AKT(PKB)
also phosphorylates and inhibits the Tuberous sclerosis 1
(Hamartin)- Tuberous sclerosis 2
(Tuberin) complex to relieve its inhibitory
action on the FK506 binding protein 12-rapamycin associated protein 1
(mTOR), which phosphorylates Eukaryotic translation
initiation factor 4E binding protein 1 (4E-BP1) and this
event allow to formed active eIF-4F complex for initiation
translation . Activation of mTOR pathway by
Insulin suppresses autophagy .
AKT(PKB) is also involved in regulating fatty acid
synthesis and lipolysis. AKT directly activates key enzymes in fatty acid synthesis - ATP
citrate lyase (ACLY) and inhibits of key enzyme in lipolysis
- Lipase, hormone-sensitive (LIPS).
Insulin induced AKT(PKB)
activity also leads to glucose transporter mobilization and glucose uptake
in several tissues., .
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