H-Ras, Rac1, AKT(PKB), PP2A catalytic, cyclin D1, PIP2, Shc, IRS-1, 220.127.116.11, HPD, Ca(II) channels, Grb2, P38 MAPK, PKA-reg (cAMP-dependent), Calmodulin, Ca(II), PKA-cat (cAMP-dependent), Galpha(s)-specific amine GPCRs, ATP, CaMK II, PP1-cat, c-Raf-1, PIP3, SOS, 18.104.22.168, PI3K reg class IA, p90RSK, MLK3(MAP3K11), IGF-1 receptor, LDHA, MSK1/2(RPS6KA5/4), cAMP, cPKC (conventional), PDK (PDPK1), CDO1, MEK1(MAP2K1), G-protein alpha-s, Adenylate cyclase type I, CaMK IV, PI3K cat class IA, ERK1/2, CREB1, Ca(II)
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 neuronal activity.
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 Ca2+/ Calmodulin complex increases. Ca2+/ Calmodulin complex binds and activates the CaMK family of serine/threonine kinases CaMKII and CaMKIV. The latter kinases phosphorylate CREB1 .
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 CaMKIV -mediated CREB1 phosphorylation .
Another pathway that may contribute to Ca(2+) -dependent stimulation of CREB1 is the Ras/MAPK pathway. Conventional isoforms of p rotein 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 .
M any 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 ( PI(3,4,5)P3 ). PI(3,4,5)P3 associates with the inner surface of the membrane and promotes the recruitment of RAC-alpha serine/threonine kinase ( AKT ) to its substrates .