Pathway Map Details

Translation_Translation regulation by Alpha-1 adrenergic receptors



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Object list (links open in MetaCore):

PtdIns(3,4,5)P3, PKC-delta, PI3K reg class IA (p85-alpha), Phosphatidylcholine, G-protein alpha-o, mTOR, RHEB2, PLC-beta1, SOS1, c-Raf-1, CaMK II, Noradrenaline extracellular region, eIF4E, VAV-2, Ca('2) cytosol, Ca('2+) endoplasmic reticulum, G-protein alpha-q, MEK1(MAP2K1), PLD2, 3.1.4.11, PRK1, MEK2(MAP2K2), PKC-epsilon, Alpha-1A adrenergic receptor, p70 S6 kinase1, c-Src, RhoA, IP3, H-Ras, p70 S6 kinase2, IP3 receptor, PI3K cat class IA (p110-beta), G-protein beta/gamma, Alpha-1D adrenergic receptor, 3.1.4.4, PtdIns(4,5)P2, G-protein alpha-11, Alpha-1B adrenergic receptor, 2.7.1.153, eEF2K, Phosphatidic acid, DAG, Shc, Pyk2(FAK2), eIF4G1/3, Tuberin, ERK2 (MAPK1), None, eIF4A, eEF2, PLD1, 1,2-diacyl-glycerol 3-phosphate, 4E-BP1, Calmodulin

Description:

Translation regulation by Alpha-1 adrenergic receptors

Subtype alpha-1 adrenergic receptors consist of Alpha-1A adrenergic receptor, Alpha-1B adrenergic receptor and Alpha-1D adrenergic receptor. Noradrenaline -activated alpha-1 adrenergic receptors participate in many physiological processes, e.g., in translation activation [1], [2], [2]

These adrenergic receptors activate different Guanine nucleotide binding proteins (G-proteins). For example, all three receptors interact with G-protein alpha-q and G-protein alpha-11 [3], [4], [1]. Alpha-1B adrenergic receptor acts through G-protein beta/gamma of pertussis toxin-sensitive Alpha activating activity polypeptide O ( G-protein alpha-o ) [3], [5]. G-proteins also activate Phospholipase C beta 1 ( PLC-beta1 ) [6]. PLC-beta1 hydrolyzes Phosphatidylinositol-4,5-bisphosphate ( PtdIns(4,5)P2 ) to produce Inositol 1,4,5-trisphosphate ( IP3 ) and 1,2-diacyl-glycerol ( DAG ).

IP3 interacts with Inositol 1,4,5-triphosphate receptor type 3 ( IP3 receptor ) of the endoplasmic reticulum, and this leads to Ca('2+) release. Elevated Ca('2+) level activates Calmodulin/ Calcium/calmodulin-dependent protein kinase II ( CaMK II )/ PTK2B protein tyrosine kinase 2 beta ( Pyk2(FAK2) )/ v-src sarcoma viral oncogene homolog ( c-Src ) [7]. c-Src can activate Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) ( PI3K reg class IA (p85-alpha) )/ PI3K cat class IA (p110-beta) directly [4], [8], [9] or via SHC (Src homology 2 domain containing) transforming protein 1 ( Shc )/ Son of sevenless homolog ( SOS )/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) [4].

Activated PI3K catalyzes transformation of PtdIns(4,5)P2 to Phosphatidylinositol-3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ). Presumably, then PtdIns(3,4,5)P3 then activates Shc/ SOS/ H-Ras. H-Ras then activates v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1(MAP2K1) and MEK2(MAP2K2) )/ Mitogen activated protein kinase 1 ( ERK2(MAPK1) ) [10], [1].

In addition, Protein kinase C, delta and epsilon ( PKC-delta and PKC-epsilon ) are believed to be activated by DAG [5], [11] and can stimulate Pyk2(FAK2)/ PI3K/ ERK2(MAPK1) [10], [8], [1] .

ERK2(MAPK1) activates Tuberous sclerosis 2 ( Tuberin ) [12]/ Ras homolog enriched in brain ( RHEB2 )/ FK506 binding protein 12-rapamycin associated protein 1 ( mTOR )/ Ribosomal protein S6 kinase 70kDa polypeptide 1 and 2 ( p70 S6 kinase1 and p70 S6 kinase2 )/ Eukaryotic elongation factor-2 kinase ( eEF2K )/ Eukaryotic translation elongation factor 2 ( eEF2 ).

Also, mTOR activates Eukaryotic translation initiation factor 4E binding protein 1 ( 4E-BP1 ) release from Eukaryotic translation initiation factor 4E ( eIF4E ) that in turn activates group Eukaryotic translation initiation factor 4 gamma ( eIF4G1/3 )/ Eukaryotic translation initiation factor 4A ( eIF4A ) [10], [1], [13]. PKC-delta seems participate in activation of mTOR and inhibition of 4E-BP1 [11]. PKC-delta phosphorylates 4E-BP1 synergistically with mTOR [14].

Moreover, Alpha-1A adrenergic receptor may participate in protein synthesis stimulation via Pyk2(FAK2) )/ c-Src/ Phospholipase D1 and D2 pathway ( PLD1 and PLD2 ) [15], [16]. PLD1 and PLD2 participate in reaction of Phosphatidic acid production, which then activates mTOR, thus stimulating translation via eEF2 and/or eIF4A [16], [13].

References:

  1. Wang L, Proud CG
    Ras/Erk signaling is essential for activation of protein synthesis by Gq protein-coupled receptor agonists in adult cardiomyocytes. Circulation research 2002 Nov 1;91(9):821-9
  2. Zhang Y, Yan J, Chen K, Song Y, Lu Z, Chen M, Han C, Zhang Y
    Different roles of alpha1-adrenoceptor subtypes in mediating cardiomyocyte protein synthesis in neonatal rats. Clinical and experimental pharmacology & physiology 2004 Sep;31(9):626-33
  3. Gurdal H, Seasholtz TM, Wang HY, Brown RD, Johnson MD, Friedman E
    Role of G alpha q or G alpha o proteins in alpha 1-adrenoceptor subtype-mediated responses in Fischer 344 rat aorta. Molecular pharmacology 1997 Dec;52(6):1064-70
  4. Hu ZW, Shi XY, Lin RZ, Hoffman BB
    Contrasting signaling pathways of alpha1A- and alpha1B-adrenergic receptor subtype activation of phosphatidylinositol 3-kinase and Ras in transfected NIH3T3 cells. Molecular endocrinology (Baltimore, Md.) 1999 Jan;13(1):3-14
  5. Ponicke K, Heinroth-Hoffmann I, Becker K, Osten B, Brodde OE
    Gq/11-coupled receptors and protein synthesis in rat cardiomyocytes: role of Gi-proteins and protein kinase C-isozymes. Naunyn-Schmiedeberg's archives of pharmacology 1999 Sep;360(3):301-8
  6. Arthur JF, Matkovich SJ, Mitchell CJ, Biden TJ, Woodcock EA
    Evidence for selective coupling of alpha 1-adrenergic receptors to phospholipase C-beta 1 in rat neonatal cardiomyocytes. The Journal of biological chemistry 2001 Oct 5;276(40):37341-6
  7. Della Rocca GJ, van Biesen T, Daaka Y, Luttrell DK, Luttrell LM, Lefkowitz RJ
    Ras-dependent mitogen-activated protein kinase activation by G protein-coupled receptors. Convergence of Gi- and Gq-mediated pathways on calcium/calmodulin, Pyk2, and Src kinase. The Journal of biological chemistry 1997 Aug 1;272(31):19125-32
  8. Gentili C, Morelli S, Russo De Boland A
    Involvement of PI3-kinase and its association with c-Src in PTH-stimulated rat enterocytes. Journal of cellular biochemistry 2002;86(4):773-83
  9. Kubo H, Hazeki K, Takasuga S, Hazeki O
    Specific role for p85/p110beta in GTP-binding-protein-mediated activation of Akt. The Biochemical journal 2005 Dec 15;392(Pt 3):607-14
  10. Wang L, Gout I, Proud CG
    Cross-talk between the ERK and p70 S6 kinase (S6K) signaling pathways. MEK-dependent activation of S6K2 in cardiomyocytes. The Journal of biological chemistry 2001 Aug 31;276(35):32670-7
  11. Wang L, Rolfe M, Proud CG
    Ca(2+)-independent protein kinase C activity is required for alpha1-adrenergic-receptor-mediated regulation of ribosomal protein S6 kinases in adult cardiomyocytes. The Biochemical journal 2003 Jul 15;373(Pt 2):603-11
  12. Ma L, Chen Z, Erdjument-Bromage H, Tempst P, Pandolfi PP
    Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005 Apr 22;121(2):179-93
  13. Averous J, Proud CG
    When translation meets transformation: the mTOR story. Oncogene 2006 Oct 16;25(48):6423-35
  14. Kumar V, Pandey P, Sabatini D, Kumar M, Majumder PK, Bharti A, Carmichael G, Kufe D, Kharbanda S
    Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of translation. The EMBO journal 2000 Mar 1;19(5):1087-97
  15. Rybkin II, Cross ME, McReynolds EM, Lin RZ, Ballou LM
    alpha(1A) adrenergic receptor induces eukaryotic initiation factor 4E-binding protein 1 phosphorylation via a Ca(2+)-dependent pathway independent of phosphatidylinositol 3-kinase/Akt. The Journal of biological chemistry 2000 Feb 25;275(8):5460-5
  16. Ballou LM, Jiang YP, Du G, Frohman MA, Lin RZ
    Ca(2+)- and phospholipase D-dependent and -independent pathways activate mTOR signaling. FEBS letters 2003 Aug 28;550(1-3):51-6