MEKK4(MAP3K4), PKA-reg (cAMP-dependent), TCF7L2 (TCF4), PI3K cat class IA, PDZ-GEF1, Adenylate cyclase type I, G-protein alpha-q/11, Ca('2+) cytosol, PKA-cat (cAMP-dependent), PtdIns(4,5)P2, PtdIns(3,4,5)P3, Elk-1, RAP-1A, Beta-catenin, MEK2(MAP2K2), cAMP, CDC42, BETA-PIX, PtdIns(4,5)P2, DAG, MEK1(MAP2K1), CREB1, Adenosine A2b receptor, None, Shc, C/EBPbeta, IP3, 22.214.171.124, GSK3 beta, VAV-1, MEK3(MAP2K3), Adenosine extracellular region, NF-kB, PKC-epsilon, eNOS, 126.96.36.199, G-protein alpha-s, cAMP-GEFI, IL-6, GRB2, IP3 receptor, H-Ras, SOS, 188.8.131.52, p38 MAPK, Pyk2(FAK2), AKT(PKB), B-Raf, Erk (MAPK1/3), Ca('2+) endoplasmic reticulum lumen, PLC-beta
Adenosine A2B receptor signaling
Adenosine A2B receptor influences cell differentiation and proliferation. A2B receptors are G-protein-coupled receptors coupling to classical second messenger pathways, such as modulation of Cyclic Adenosine 3',5'-phosphate ( cAMP ) production or the Phospholipase C ( PLC ) pathway.
Adenosine A2B receptor interacts with trimeric G-protein alpha-s/G-protein beta/gamma and G-protein alpha-q/ G-protein beta/gamma. This causes exchange of GDP for GTP bound to G protein alpha subunits and subsequent dissociation of G-protein beta/gamma heterodimers.
G-protein alpha-s activates Adenylate cyclase I, which then increases levels of cAMP in the cell and activates Protein kinase cAMP-dependent ( PKA ) inactive complex that results in the activation of PKA . In turn, PKA phosphorylates and inactivates Glycogen synthase kinase 3 beta ( GSK3 beta ) , which leads to attenuation of Beta-catenin inhibition. Consequently, this signaling cascade activates cell cycle progression, initiating activity of Transcription factor 7-like 2 ( TCF7L2 (TCF4) ) that promotes the expression of Cyclin D1 and V-myc myelocytomatosis viral oncogene homolog (c-Myc) . Phosphorylation and activation of cAMP responsive element binding protein 1 ( CREB1 ) is mainly mediated via adenosine Adenosine A2B receptor .
Adenosine stimulates Interleukin 6 ( IL-6) expression in human astrocytoma cell lines via Adenosine A2B receptor inducing p38 mitogen-activated protein kinases ( p38MAPK ). G-protein alpha-q/11 activates Phospholipase C beta ( PLC-beta ). PLC-beta catalyzes hydrolysis of Phosphoinositide 4,5-bisphosphate ( PI(4,5)P2 ) into Inositol 1,4,5-triphosphate ( IP3 ) and Diacylglycerol ( DAG ). IP3 released into the cytoplasm mobilizes Ca(II) from internal stores, whereas DAG activates Protein kinase C epsilon ( PKC-epsilon ). PKC-epsilon induces PTK2B protein tyrosine kinase 2 beta (PYK2) activation and stimulation of PKC-epsilon/ PYK2/Vav 1 guanine nucleotide exchange factor ( VAV-1 )/ Cell division cycle 42 ( Cdc42 )/ M itogen-activated protein kinase kinase kinase 4 ( MEKK4 )/Mitogen-activated protein kinase kinase 3 ( MEK3 ) pathway . Stimulation of Adenosine A2B receptor can activate p38MAPK via cAMP/ PKA/ Rho guanine nucleotide exchange factor 7 ( BETA-PIX ) pathway . p38MAPK, possibly Nuclear factor kappa B ( NF-kB ), and CCAAT/enhancer binding protein beta ( C/EBPbeta ) activate transcription of IL-6 .
Human Adenosine A2B receptors mediate phosphorylation and activation of the Extracellular signal-regulated kinase ( ERK ) via cAMP/Rap guanine nucleotide exchange factor 3 ( AMP-GEF1 )/RAP1A member of RAS oncogene family ( RAP-1A )/Small nuclear ribonucleoprotein polypeptide E ( B-Raf ) pathway .
Adenosine induces NO production by Nitric oxide synthase 3 ( eNOS ), whose activation is initiated by Phosphoinositide-3-kinase ( PI3K )/V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB) ) pathway and ERK/ ELK1 member of ETS oncogene family ( Elk-1 )-dependent transcription. Upon activation by cAMP, guanine nucleotide exchange factor Rap guanine nucleotide exchange factor 2 (PDZ-GEF ) stimulates PI3K activation via v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ). PI3K converts Phosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 ) to Phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) . PtdIns(3,4,5)P3 is a second messenger that directly binds to and AKT. AKT phosphorylates and activates eNOS .