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Transcription CREB pathway

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Transcription CREB pathway

CREB signaling pathway

Extracellular stimuli elicit changes in gene expression in target cells by activatingintracellular protein kinase cascades that phosphorylate transcription factors within thenucleus. One of the best characterized stimulus-induced transcription factors is cyclicAMP (cAMP) responsive element binding protein 1 ( CREB1 ). CREB1 iscritical for a variety of cellular processes, including proliferation, differentiation,and adaptive responses. CREB family members are believed to be important for learning andmemory and contribute to neuronal adaptation to drugs of abuse and hormonal control ofmetabolic processes, including regulation of gluconeogenesis by hormones glucagon andinsulin [1].

CREB1 activates transcription of the target genes in response to a diversearray of stimuli, including peptide hormones, growth factors, and neuronal activity.

CREB1 activation is induced through phosphorylation mediated by kinases, suchas 1 ) Cyclic AMP-dependent protein kinase A ( PKA ), 2 ) Calcium-calmodulinkinase II ( CaMKII ) and IV ( CaMK IV ), 3 ) Protein kinase C ( PKC), 4 ) MAPK ERK-activated kinase p90RSK, 5 ) p38 MAPK-activated mitogen- andstress-activated protein kinase 1 ( MSK1 ), and 6 ) Phosphatidylinositol 3-kinase( PI3K ) activated AKT ( PKB). Activities of these kinases areunder tight control of various cellular stimuli.

Stimulation of G protein-coupled receptors leads to the activation of coupledheterotrimeric G-proteins. The latter contain activated alpha (s) subunits ( G-proteinalpha-s ) that stimulate one or more isoforms of Adenylate cyclase, an enzymethat catalyzes cyclic AMP ( cAMP ) production. In most cells, the primary targetof 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 inhibitoryeffect and thereby activates PKA-cat (cAMP-dependent). PKA-mediated CREB1phosphorylation is the most predominant mechanism of CREB1 activation [2].

Ca(2+) -signaling pathways also mediate CREB1 phosphorylation. Whenintracellular Ca(2+) concentration rises, the concentration of Ca2+/Calmodulin complex increases. Ca2+/ Calmodulin complex binds andactivates the CaMK family of serine/threonine kinases CaMKII and CaMKIV.The latter kinases phosphorylate CREB1 [3].

CREB1 dephosphorylation is one way of control of the duration of Ca(2+)-induced CREB1 phosphorylation. Such dephosphorylation of CREB1 can becatalyzed by the protein phosphatase PP1 ( PP1-cat ). The CaMKIV-associated protein phosphatase PP2A ( PP2A catalytic ) dephosphorylatesCaMKIV and thereby terminates CaMKIV -mediated CREB1 phosphorylation[4].

Another pathway that may contribute to Ca(2+) -dependent stimulation ofCREB1 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 PKCcan phosphorylate and activate serine/threonine protein kinase v-Raf-1 murine leukemiaviral oncogene homolog 1 ( c-Raf-1 ). That leads to stimulation of thec-Raf-1/ Mitogen-activated protein kinase kinase 1 ( MEK1 )/Mitogen-activated protein kinases 1 and 3 ( ERK1/2 ) cascade [5].

M any studies have also documented that MAPK signaling pathway can play a role in theactivation of CREB1. Insulin-like growth factors stimulates the Insulin-likegrowth factor 1 receptor ( IGF-1 receptor ) that, via adaptors proteins Insulinreceptor substrate 1 ( IRS-1 ), Src homology 2 domain containing transformingprotein ( Shc ) and Growth factor receptor bound 2 ( GRB2 ), can stimulateguanine-nucleotide exchange factor Son of sevenless proteins ( SOS ) and activatesmall 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 MAPkinases ERK1/2. One of the substrate of ERK1/2 is the 90-kDa ribosomalprotein SG kinase ( p90RSK ) [6]. Both ERK1/2 andp90RSK translocate upon activation to the nucleus where p90RSK canphosphorylate CREB1. All three p90RSK family members (RSK1-3) canphosphorylate CREB1 [6].

In addition to activating ERK1/2 and p90RSK, small GTPase Rac1stimulates p38 MAPK pathway via MEKK1 kinase. The p38 MAPK gets activatedby 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[7], [8].

Various growth factor receptors activate PI3K pathway through recruitment of theadaptor protein IRS1. PI3K cat class IA converts Phosphatidylinositol4,5-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 themembrane and promotes the recruitment of RAC-alpha serine/threonine kinase ( AKT )to its substrates [9].