Development - Alpha-2 adrenergic receptor activation of ERK

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Alpha-2 adrenergic receptor activation of ERK

Alpha-2A adrenergic receptor, Alpha-2B adrenergic receptor, and Alpha-2C-1 adrenergic receptor participate in activation of Mitogen-activated protein kinases 1 and 3 (ERK1/2) via different ways [1].

Alpha-2A adrenergic receptor activates Phospholipase C beta 3 or 2 (PLC-beta3 or PLC-beta2) when complex Guanine nucleotide binding protein (G protein) beta and gamma (G-protein beta/gamma) is released from the trimeric complex with G-protein alpha-i family (presumably by G-protein alpha-i2) [2], [3]. PLC-beta3 and PLC-beta2 may to hydrolyze Phosphatidylinositol-4,5-Bisphosphate (PtdIns(4,5)P2) and produce 1,2-diacyl-glycerol (DAG) and Inositol 1,4,5-trisphosphate (IP3). IP3 activates Inositol 1,4,5-triphosphate receptor type 3 (IP3 receptor), which causes Ca('2) release from intracellular compartments. As a result of activation of adrenergic receptor, elevated cytosolic Ca('2) levels lead to activation of Calmodulin/ most likely Calcium/calmodulin-dependent protein kinase II (CaMK II)/ PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2))/ v-src sarcoma viral oncogene homolog (c-Src)/ SHC transforming protein 1 (Shc)/ Growth factor receptor-bound protein 2 (GRB2)/ son of sevenless homolog (SOS)/ v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras)/ v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)/ Mitogen-activated protein kinase kinase 1 and 2 (MEK1 and MEK2)/ Erk [2].

Also, activation of ERK cascade by all three Alpha-2 adrenergic receptors is accomplished by stimulation of Arachidonic acid production via DAG. DAG is catalyzed by Diacylglycerol lipase alpha and beta (DGL-alpha and DGL-beta) to 2-arachidonoylglycerol, which gets converted by Monoglyceride lipase to Arachidonic acid. Arachidonic acid is then converted by Cytochrome P450 (by, for instance, Cytochrome P450 family 2 subfamily C polypeptide 8 (CYP2C8)) to 14,15-epoxyeicosatrienoic acid (cis-14,15-Epoxyeicosatrienoic acid), which activates c-Src. c-Src may phosphorylate matrix metalloproteinases, for example ADAM metallopeptidase domain 12 (ADAM12). ADAM12, in turn, cleaves Heparin-binding EGF-like growth factor (HB-EGF) leading to transactivation of Epidermal growth factor receptor (EGFR). EGFR then activates Shc- and GRB2-mediated ERK cascade activation [1].

In addition, Alpha-2A and Alpha-2C-1 adrenergic receptors, after activation of c-Src, can activate Shc/ GRB2/ SOS without EGFR-transactivation [1].

Also, all three Alpha-2 adrenergic receptors stimulate v-akt murine thymoma viral oncogene homolog (AKT(PKB)) that is thought to activate ERK2 and ERK1. AKT(PKB) may act via EGFR/ Phosphoinositide-3-kinase (PI3K) / PtdIns(3,4,5)P3/ possibly via GRB2-associated binding protein 1 (GAB1) or directly/ 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1)/ AKT. Alpha-2A and Alpha-2C-1 adrenergic receptors are also able to activate Phosphoinositide-3-kinase, regulatory subunit 1 (p85 alpha) (PI3K reg class IA (p85-alpha)) via c-Src without EGFR transactivation [1], [4], [5].

Moreover, Alpha-2B adrenergic receptor participates in ERK activation via extracellular Ca('2+) dependent Phospholipase A2 (cPLA2) activation, which in turn lead to Arachidonic acid production and to the above-described ERK cascade activation via Shc [6].

Due to ERK activity, adrenergic receptors influence cell growth and proliferation [1], [6]. Furthermore, in nerve cells, ERK activates Jun oncogene (c-Jun) and participates in cell differentiation [7].

References:

  1. Karkoulias G, Mastrogianni O, Lymperopoulos A, Paris H, Flordellis C
    alpha(2)-Adrenergic receptors activate MAPK and Akt through a pathway involving arachidonic acid metabolism by cytochrome P450-dependent epoxygenase, matrix metalloproteinase activation and subtype-specific transactivation of EGFR. Cellular signalling 2006 May;18(5):729-39
  2. 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
  3. Dorn GW 2nd, Oswald KJ, McCluskey TS, Kuhel DG, Liggett SB
    Alpha 2A-adrenergic receptor stimulated calcium release is transduced by Gi-associated G(beta gamma)-mediated activation of phospholipase C. Biochemistry 1997 May 27;36(21):6415-23
  4. Pace AM, Faure M, Bourne HR
    Gi2-mediated activation of the MAP kinase cascade. Molecular biology of the cell 1995 Dec;6(12):1685-95
  5. Chen X, Resh MD
    Cholesterol depletion from the plasma membrane triggers ligand-independent activation of the epidermal growth factor receptor. The Journal of biological chemistry 2002 Dec 20;277(51):49631-7
  6. Cussac D, Schaak S, Gales C, Flordellis C, Denis C, Paris H
    alpha(2B)-Adrenergic receptors activate MAPK and modulate proliferation of primary cultured proximal tubule cells. American journal of physiology. Renal physiology 2002 May;282(5):F943-52
  7. Taraviras S, Olli-Lahdesmaki T, Lymperopoulos A, Charitonidou D, Mavroidis M, Kallio J, Scheinin M, Flordellis C
    Subtype-specific neuronal differentiation of PC12 cells transfected with alpha2-adrenergic receptors. European journal of cell biology 2002 Jun;81(6):363-74

  1. Karkoulias G, Mastrogianni O, Lymperopoulos A, Paris H, Flordellis C
    alpha(2)-Adrenergic receptors activate MAPK and Akt through a pathway involving arachidonic acid metabolism by cytochrome P450-dependent epoxygenase, matrix metalloproteinase activation and subtype-specific transactivation of EGFR. Cellular signalling 2006 May;18(5):729-39
  2. 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
  3. Dorn GW 2nd, Oswald KJ, McCluskey TS, Kuhel DG, Liggett SB
    Alpha 2A-adrenergic receptor stimulated calcium release is transduced by Gi-associated G(beta gamma)-mediated activation of phospholipase C. Biochemistry 1997 May 27;36(21):6415-23
  4. Pace AM, Faure M, Bourne HR
    Gi2-mediated activation of the MAP kinase cascade. Molecular biology of the cell 1995 Dec;6(12):1685-95
  5. Chen X, Resh MD
    Cholesterol depletion from the plasma membrane triggers ligand-independent activation of the epidermal growth factor receptor. The Journal of biological chemistry 2002 Dec 20;277(51):49631-7
  6. Cussac D, Schaak S, Gales C, Flordellis C, Denis C, Paris H
    alpha(2B)-Adrenergic receptors activate MAPK and modulate proliferation of primary cultured proximal tubule cells. American journal of physiology. Renal physiology 2002 May;282(5):F943-52
  7. Taraviras S, Olli-Lahdesmaki T, Lymperopoulos A, Charitonidou D, Mavroidis M, Kallio J, Scheinin M, Flordellis C
    Subtype-specific neuronal differentiation of PC12 cells transfected with alpha2-adrenergic receptors. European journal of cell biology 2002 Jun;81(6):363-74

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