Pathway maps

Development_A2B receptor: action via G-protein alpha s
Development_A2B receptor: action via G-protein alpha s

Object List (links open in MetaCore):

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, 2.7.1.137, GSK3 beta, VAV-1, MEK3(MAP2K3), Adenosine extracellular region, NF-kB, PKC-epsilon, eNOS, 3.1.4.11, G-protein alpha-s, cAMP-GEFI, IL-6, GRB2, IP3 receptor, H-Ras, SOS, 4.6.1.1, p38 MAPK, Pyk2(FAK2), AKT(PKB), B-Raf, Erk (MAPK1/3), Ca('2+) endoplasmic reticulum lumen, PLC-beta

Description

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 [1]. 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) [2]. Phosphorylation and activation of cAMP responsive element binding protein 1 ( CREB1 ) is mainly mediated via adenosine Adenosine A2B receptor [3].

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 [4]. Stimulation of Adenosine A2B receptor can activate p38MAPK via cAMP/ PKA/ Rho guanine nucleotide exchange factor 7 ( BETA-PIX ) pathway [5]. p38MAPK, possibly Nuclear factor kappa B ( NF-kB ), and CCAAT/enhancer binding protein beta ( C/EBPbeta ) activate transcription of IL-6 [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 [5].

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 ) [7]. PtdIns(3,4,5)P3 is a second messenger that directly binds to and AKT. AKT phosphorylates and activates eNOS [8].

References:

  1. Defer N, Best-Belpomme M, Hanoune J
    Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. American journal of physiology. Renal physiology. 2000 Sep;279(3):F400-16
  2. Fishman P, Madi L, Bar-Yehuda S, Barer F, Del Valle L, Khalili K
    Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells. Oncogene 2002 Jun 6;21(25):4060-4
  3. Lynge J, Schulte G, Nordsborg N, Fredholm BB, Hellsten Y
    Adenosine A 2B receptors modulate cAMP levels and induce CREB but not ERK1/2 and p38 phosphorylation in rat skeletal muscle cells. Biochemical and biophysical research communications 2003 Jul 18;307(1):180-7
  4. Fiebich BL, Akundi RS, Biber K, Hamke M, Schmidt C, Butcher RD, van Calker D, Willmroth F
    IL-6 expression induced by adenosine A2b receptor stimulation in U373 MG cells depends on p38 mitogen activated kinase and protein kinase C. Neurochemistry international 2005 May;46(6):501-12
  5. Schulte G, Fredholm BB
    The G(s)-coupled adenosine A(2B) receptor recruits divergent pathways to regulate ERK1/2 and p38. Experimental cell research 2003 Oct 15;290(1):168-76
  6. Schwaninger M, Neher M, Viegas E, Schneider A, Spranger M
    Stimulation of interleukin-6 secretion and gene transcription in primary astrocytes by adenosine. Journal of neurochemistry 1997 Sep;69(3):1145-50
  7. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  8. Xu Z, Park SS, Mueller RA, Bagnell RC, Patterson C, Boysen PG
    Adenosine produces nitric oxide and prevents mitochondrial oxidant damage in rat cardiomyocytes. Cardiovascular research 2005 Mar 1;65(4):803-12