to see a detailed, interactive version of this map NOTE: PathFinder requires the Flash plug-in for proper viewing. It will launch in a separate pop-up window, please turn off any pop-up blockers for this web site. Copyright ©2006 ProteinLounge.com

 CREB Pathway

CREB (isoforms; CREB-327 and CREB-341), cAMP responsive element binding protein, is a transcription factor that is both a positive and a negative regulator of gene transcription that affects the expression of hundreds of genes depending upon cell phenotype and context. CREB forms homo- and heterodimers (with other transcription factors) that interact with DNA in gene promoters. The primary binding site of the CREB homodimer is the cAMP response element (CRE)/calcium response element (CaRE) with the general motif 5'-TGACGTCA-3'. The nuclear factor CREM, cAMP response element modulator, also binds to CRE. It acts primarily as a down-regulator of CREB. CREB homodimers are activated as gene transcription promoters by phosphorylation at Ser133 in CREB-341 and Ser119 (equivalent position to serine 133 in CREB341) in CREB-327 by protein kinases that are activated by a variety of signaling events. CREB activation is driven by the second messengers: cAMP and/or calcium. In addition, CREB activation can be driven by growth and/or stress signals that activate MAPKs pathways, involving ERK and p38MAPK signaling, respectively.

Signals that elevate intracellular calcium levels such as: membrane depolarization; calcium ion pore opening; or IP3-mediated ER release activate the calcium/calmodulin/calmodulin kinase cascade. CaMkinases I and IV phosphorylate CREB and activate gene expression. Activation of adenylyl cyclases elevates the intracellular level of cAMP which activates cAMP-dependent protein kinase A, PKA. PKA phosphorylates and activates CREB. Signals that activate the p21Ras/Raf1/MEK/ERK pathway, a growth and anti-apoptotic pathway, activate the p90 ribosomal S6 kinases (p90S6K), RSK1 and RSK2. These kinases activate CREB. Cell stress induces the MEKK/MKK/p38 pathway to activate the p90S6K kinases, MSK1 and MSK2 which phosphorylate CREB. Many factors mitigate the effect of CREB on gene expression. CREB activity can be stopped by dephosphorylation. Protein phosphatase 2A (PP2A) is a well known CREB dephosphorylase.