CREB signaling pathway
Extracellular stimuli elicit changes in gene expression in target cells by activating
intracellular protein kinase cascades that phosphorylate transcription factors within the
nucleus. One of the best characterized stimulus-induced transcription factors is cyclic
AMP (cAMP) responsive element binding protein 1 (CREB1).
CREB1 is critical for a variety of cellular processes,
including proliferation, differentiation, and adaptive responses. CREB family members are
believed to be important for learning and memory and contribute to neuronal adaptation to
drugs of abuse and hormonal control of metabolic processes, including regulation of
gluconeogenesis by hormones glucagon and insulin .
CREB1 activates transcription of the target genes in
response to a diverse array of stimuli, including peptide hormones, growth factors, and
CREB1 activation is induced through phosphorylation
mediated by kinases, such as 1) Cyclic AMP-dependent protein kinase A
(PKA), 2) Calcium-calmodulin kinase II
(CaMKII) and IV (CaMK IV), 3)
Protein kinase C (PKC), 4) MAPK ERK-activated kinase
p90RSK, 5) p38 MAPK-activated mitogen- and stress-activated
protein kinase 1 (MSK1), and 6) Phosphatidylinositol
3-kinase (PI3K) activated
AKT(PKB). Activities of these
kinases are under tight control of various cellular stimuli.
Stimulation of G protein-coupled receptors leads to the activation of coupled
heterotrimeric G-proteins. The latter contain activated alpha (s) subunits
(G-protein alpha-s) that stimulate one or more isoforms of
Adenylate cyclase, an enzyme that catalyzes cyclic AMP
(cAMP) production. In most cells, the primary target of
cAMP is the cAMP-dependent protein kinase (PKA). In the
absence of cAMP, PKA exists as an inactive heterotetramer of
two catalytic subunits (PKA-cat (cAMP-dependent)) bound to
two regulatory subunits (PKA-reg (cAMP-dependent)). The
binding of cAMP to PKA-reg (cAMP-dependent)
abolishes its inhibitory effect and thereby activates
PKA-cat (cAMP-dependent). PKA-mediated
CREB1 phosphorylation is the most predominant mechanism of
CREB1 activation .
Ca(2+)-signaling pathways also mediate
CREB1 phosphorylation. When intracellular
Ca(2+) concentration rises, the concentration of
complex binds and activates the CaMK family of serine/threonine kinases
CaMKII and CaMKIV. The latter
kinases phosphorylate CREB1 . In addition
Ca2+ binding to Kv channel interacting protein 3, calsenilin
(DREAM) impairs its interaction with
CREB1 and therefore deprepresses
CREB1 transcriptional activity which is repressed by
DREAM - CREB1 interaction
CREB1 dephosphorylation is one way of control of the
duration of Ca(2+)-induced
CREB1 phosphorylation. Such dephosphorylation of
CREB1 can be catalyzed by the protein phosphatase
PP1 (PP1-cat). The
CaMKIV-associated protein phosphatase PP2A
(PP2A catalytic) dephosphorylates
CaMKIV and thereby terminates
Another pathway that may contribute to Ca(2+)-dependent
stimulation of CREB1 is the Ras/MAPK pathway. Conventional
isoforms of protein kinase C, alpha, beta and gamma (cPKC),
are activated by Ca(2+). These isoforms of PKC can
phosphorylate and activate serine/threonine protein kinase v-Raf-1 murine leukemia viral
oncogene homolog 1 (c-Raf-1). That leads to stimulation of
the c-Raf-1/ Mitogen-activated protein kinase kinase 1
(MEK1)/ Mitogen-activated protein kinases 1 and 3
(ERK1/2) cascade .
Many studies have also documented that MAPK signaling pathway can play a role in the
activation of CREB1. Insulin-like growth factors stimulates
the Insulin-like growth factor 1 receptor (IGF-1 receptor)
that, via adaptors proteins Insulin receptor substrate 1
(IRS-1), Src homology 2 domain containing transforming
protein (Shc) and Growth factor receptor bound 2
(GRB2), can stimulate guanine-nucleotide exchange factor Son
of sevenless proteins (SOS) and activate small GTPase
v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras).
Activated H-Ras interacts with and stimulates the protein
kinase c-Raf-1. The latter sequentially triggers and
activates the MEK1 kinase and its target MAP
kinases ERK1/2. One of the substrate of ERK1/2
is the 90-kDa ribosomal protein SG kinase
(p90RSK) . Both ERK1/2
and p90RSK translocate upon activation to the
nucleus where p90RSK can phosphorylate
CREB1. All three p90RSK family
members (RSK1-3) can phosphorylate CREB1 .
In addition to activating ERK1/2 and
p90RSK, small GTPase Rac1
stimulates p38 MAPK pathway via MEKK1 kinase.
The p38 MAPK gets activated by the upstream kinases
Mitogen-activated protein kinase kinase 3 and/or 6 (MEK3/6)
and catalyzes the phosphorylation and activation of two kinases,
MSK1 and MSK2.
MSK1 and MSK2 phosphorylate
CREB1 , .
Various growth factor receptors activate PI3K pathway through recruitment of the
adaptor protein IRS1. PI3K cat class IA
converts Phosphatidylinositol 4,5-biphosphate
(PI(4,5)P2) to Phosphatidylinositol 3,4,5-triphosphate
associates with the inner surface of the membrane and promotes the recruitment of
RAC-alpha serine/threonine kinase (AKT) to its substrates
The activated AKT induces phosphorylation of
CREB1 and stimulates target gene expression via
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