Pathway maps

Translation_Translation regulation by Alpha-1 adrenergic receptors
Translation_Translation regulation by Alpha-1 adrenergic receptors

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,, 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,, PtdIns(4,5)P2, G-protein alpha-11, Alpha-1B adrenergic receptor,, 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


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].


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    Specific role for p85/p110beta in GTP-binding-protein-mediated activation of Akt. The Biochemical journal 2005 Dec 15;392(Pt 3):607-14
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    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
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    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
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    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
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    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
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    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
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    Ca(2+)- and phospholipase D-dependent and -independent pathways activate mTOR signaling. FEBS letters 2003 Aug 28;550(1-3):51-6