Development - Beta-adrenergic receptors regulation of ERK

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Beta-adrenergic receptor-induced regulation of ERK

Beta-1, Beta-2 and Beta-3 adrenergic receptors can activate Mitogen-activated protein kinase 1 and 3 (Erk (MAPK1/3)) phosphorylation in v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) - dependent and independent manner with various physiological effects, such as cardiomyocytes hypertrophy [1], cell growth and development [2], proliferation [3], cell migration [4], and long-term potentiation in neurons [5].

For example, Beta-2 adrenergic receptor activate GNAS complex locus (G-protein alpha-s)/ Adenylate cyclases, which leads to Adenosine 3',5'-cyclic phosphate (cAMP) production. This activates Protein kinase cAMP-dependent regulatory (PKA-reg (cAMP-dependent) and catalytic (PKA-cat (cAMP-dependent)) subunits. PKA-cat activates RAP1A member of RAS oncogene family (RAP-1A)/ v-raf murine sarcoma viral oncogene homolog B1 (B-Raf)/ Mitogen-activated protein kinase kinase 2 and 1 (MEK2(MAP2K2) and MEK1(MAP2K1))/ Erk [6]. In addition, Beta adrenergic receptor-dependent cytosolic redistribution of RAP-1A may participate, for example, in parotid gland secretion [7]. It is shown, that PKA-activated Erk takes part in cardiomyocytes hypertrophy in normal and pathological processes [1].

It is also known that cAMP levels may be regulated via beta-arrestin-dependent signaling [8].

In addition, Beta adrenergic receptor may inhibit Erk (stimulated by Beta adrenergic or other receptors), possibly, via PKA/ v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) cascade [9], [10], [11].

PKA-cat phosphorylation of Beta-2 adrenergic receptor leads to its activation switch from G-protein alpha-i family to G-protein alpha-s. G-protein alpha-i family activation releases complex of G-protein beta/gamma, which activates c-src tyrosine kinase (c-Src) [12]. Moreover, Beta-3 adrenergic receptor can activate c-Src directly [13]. c-Src phosphorylates SHC transforming protein 1 (Shc) and Growth factor receptor-bound protein 2 (GRB2), activating Son of sevenless homolog (SOS)/ H-Ras/ c-Raf-1 and subsequent MEK and Erk activation [12], [13].

Additionally, cAMP activates Erk in PKA-independent manner via Rap guanine nucleotide exchange factor 3 (cAMP-GEFI)/ RAP2B member of RAS oncogene family (RAP-2B) or RAP-1A/ Phospholipase C epsilon 1 (PLC-epsilon) [14], [15], [16]. PLC-epsilon catalyzes transformation of Phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to 1,2-diacyl-glycerol (DAG) and Inositol 1,4,5-trisphosphate (IP3). IP3 activates Inositol 1,4,5-triphosphate receptor type 3 (IP3 receptor)-mediated Ca('2+) release from endoplasmic reticulum [14], [15]. Ca('2+) and DAG activate RAS guanyl releasing protein 1 (CalDAG-GEFII), which triggers H-Ras / c-Raf-1 / MEK / Erk activation [15]. It has been shown that cAMP-GEFI-activated Erk may participate in cell growth and development via adhesion molecule CD44 in salivary gland cells [2].

Beta-1 adrenergic receptor may also stimulate Rap guanine nucleotide exchange factor (GEF) 2 (PDZ-GEF1) directly and/or via cAMP. PDZ-GEF1/ H-Ras cascade leads to Erk activation [17].

Beta-2 adrenergic receptor may activate adult cell proliferation via some Phosphoinositide-3-kinase (PI3K)-dependent pathway, possibly G-protein beta/gamma/ PI3K/ PtdIns(3,4,5)P3/ 3-phosphoinositide dependent protein kinase-1 (PDK (PDPK1))/ MEK / Erk cascade [3], [18].

Beta-2 adrenergic receptor may inhibit migration of keratinocyte via G-protein alpha-s/ cAMP-dependent activation of Protein phosphatase 2 (PP2A), which inhibits Epidermal growth factor receptor (EGFR)-transactivated Erk [4].

References:

  1. Yamazaki T, Komuro I, Zou Y, Kudoh S, Shiojima I, Hiroi Y, Mizuno T, Aikawa R, Takano H, Yazaki Y
    Norepinephrine induces the raf-1 kinase/mitogen-activated protein kinase cascade through both alpha 1- and beta-adrenoceptors. Circulation 1997 Mar 4;95(5):1260-8
  2. Yeh CK, Ghosh PM, Dang H, Liu Q, Lin AL, Zhang BX, Katz MS
    beta-Adrenergic-responsive activation of extracellular signal-regulated protein kinases in salivary cells: role of epidermal growth factor receptor and cAMP. American journal of physiology. Cell physiology 2005 Jun;288(6):C1357-66
  3. Pesce L, Comellas A, Sznajder JI
    Beta-adrenergic agonists regulate Na-K-ATPase via p70S6k. American journal of physiology. Lung cellular and molecular physiology 2003 Oct;285(4):L802-7
  4. Pullar CE, Chen J, Isseroff RR
    PP2A activation by beta2-adrenergic receptor agonists: novel regulatory mechanism of keratinocyte migration. The Journal of biological chemistry 2003 Jun 20;278(25):22555-62
  5. Winder DG, Martin KC, Muzzio IA, Rohrer D, Chruscinski A, Kobilka B, Kandel ER
    ERK plays a regulatory role in induction of LTP by theta frequency stimulation and its modulation by beta-adrenergic receptors. Neuron 1999 Nov;24(3):715-26
  6. Schmitt JM, Stork PJ
    beta 2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein rap1 and the serine/threonine kinase B-Raf. The Journal of biological chemistry 2000 Aug 18;275(33):25342-50
  7. D'Silva NJ, Jacobson KL, Ott SM, Watson EL
    Beta-adrenergic-induced cytosolic redistribution of Rap1 in rat parotid acini: role in secretion. The American journal of physiology 1998 Jun;274(6 Pt 1):C1667-73
  8. Baillie GS, Sood A, McPhee I, Gall I, Perry SJ, Lefkowitz RJ, Houslay MD
    beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proceedings of the National Academy of Sciences of the United States of America 2003 Feb 4;100(3):940-5
  9. Crespo P, Cachero TG, Xu N, Gutkind JS
    Dual effect of beta-adrenergic receptors on mitogen-activated protein kinase. Evidence for a beta gamma-dependent activation and a G alpha s-cAMP-mediated inhibition. The Journal of biological chemistry 1995 Oct 20;270(42):25259-65
  10. Graves LM, Bornfeldt KE, Raines EW, Potts BC, Macdonald SG, Ross R, Krebs EG
    Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proceedings of the National Academy of Sciences of the United States of America 1993 Nov 1;90(21):10300-4
  11. Sevetson BR, Kong X, Lawrence JC Jr
    Increasing cAMP attenuates activation of mitogen-activated protein kinase. Proceedings of the National Academy of Sciences of the United States of America 1993 Nov 1;90(21):10305-9
  12. Daaka Y, Luttrell LM, Lefkowitz RJ
    Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature 1997 Nov 6;390(6655):88-91
  13. Cao W, Luttrell LM, Medvedev AV, Pierce KL, Daniel KW, Dixon TM, Lefkowitz RJ, Collins S
    Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation. The Journal of biological chemistry 2000 Dec 8;275(49):38131-4
  14. Schmidt M, Evellin S, Weernink PA, von Dorp F, Rehmann H, Lomasney JW, Jakobs KH
    A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nature cell biology 2001 Nov;3(11):1020-4
  15. Keiper M, Stope MB, Szatkowski D, Bohm A, Tysack K, Vom Dorp F, Saur O, Oude Weernink PA, Evellin S, Jakobs KH, Schmidt M
    Epac- and Ca2+ -controlled activation of Ras and extracellular signal-regulated kinases by Gs-coupled receptors. The Journal of biological chemistry 2004 Nov 5;279(45):46497-508
  16. Oestreich EA, Wang H, Malik S, Kaproth-Joslin KA, Blaxall BC, Kelley GG, Dirksen RT, Smrcka AV
    Epac-mediated activation of phospholipase C(epsilon) plays a critical role in beta-adrenergic receptor-dependent enhancement of Ca2+ mobilization in cardiac myocytes. The Journal of biological chemistry 2007 Feb 23;282(8):5488-95
  17. Pak Y, Pham N, Rotin D
    Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation. Molecular and cellular biology 2002 Nov;22(22):7942-52
  18. Sato S, Fujita N, Tsuruo T
    Involvement of 3-phosphoinositide-dependent protein kinase-1 in the MEK/MAPK signal transduction pathway. The Journal of biological chemistry 2004 Aug 6;279(32):33759-67

  1. Yamazaki T, Komuro I, Zou Y, Kudoh S, Shiojima I, Hiroi Y, Mizuno T, Aikawa R, Takano H, Yazaki Y
    Norepinephrine induces the raf-1 kinase/mitogen-activated protein kinase cascade through both alpha 1- and beta-adrenoceptors. Circulation 1997 Mar 4;95(5):1260-8
  2. Yeh CK, Ghosh PM, Dang H, Liu Q, Lin AL, Zhang BX, Katz MS
    beta-Adrenergic-responsive activation of extracellular signal-regulated protein kinases in salivary cells: role of epidermal growth factor receptor and cAMP. American journal of physiology. Cell physiology 2005 Jun;288(6):C1357-66
  3. Pesce L, Comellas A, Sznajder JI
    Beta-adrenergic agonists regulate Na-K-ATPase via p70S6k. American journal of physiology. Lung cellular and molecular physiology 2003 Oct;285(4):L802-7
  4. Pullar CE, Chen J, Isseroff RR
    PP2A activation by beta2-adrenergic receptor agonists: novel regulatory mechanism of keratinocyte migration. The Journal of biological chemistry 2003 Jun 20;278(25):22555-62
  5. Winder DG, Martin KC, Muzzio IA, Rohrer D, Chruscinski A, Kobilka B, Kandel ER
    ERK plays a regulatory role in induction of LTP by theta frequency stimulation and its modulation by beta-adrenergic receptors. Neuron 1999 Nov;24(3):715-26
  6. Schmitt JM, Stork PJ
    beta 2-adrenergic receptor activates extracellular signal-regulated kinases (ERKs) via the small G protein rap1 and the serine/threonine kinase B-Raf. The Journal of biological chemistry 2000 Aug 18;275(33):25342-50
  7. D'Silva NJ, Jacobson KL, Ott SM, Watson EL
    Beta-adrenergic-induced cytosolic redistribution of Rap1 in rat parotid acini: role in secretion. The American journal of physiology 1998 Jun;274(6 Pt 1):C1667-73
  8. Baillie GS, Sood A, McPhee I, Gall I, Perry SJ, Lefkowitz RJ, Houslay MD
    beta-Arrestin-mediated PDE4 cAMP phosphodiesterase recruitment regulates beta-adrenoceptor switching from Gs to Gi. Proceedings of the National Academy of Sciences of the United States of America 2003 Feb 4;100(3):940-5
  9. Crespo P, Cachero TG, Xu N, Gutkind JS
    Dual effect of beta-adrenergic receptors on mitogen-activated protein kinase. Evidence for a beta gamma-dependent activation and a G alpha s-cAMP-mediated inhibition. The Journal of biological chemistry 1995 Oct 20;270(42):25259-65
  10. Graves LM, Bornfeldt KE, Raines EW, Potts BC, Macdonald SG, Ross R, Krebs EG
    Protein kinase A antagonizes platelet-derived growth factor-induced signaling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proceedings of the National Academy of Sciences of the United States of America 1993 Nov 1;90(21):10300-4
  11. Sevetson BR, Kong X, Lawrence JC Jr
    Increasing cAMP attenuates activation of mitogen-activated protein kinase. Proceedings of the National Academy of Sciences of the United States of America 1993 Nov 1;90(21):10305-9
  12. Daaka Y, Luttrell LM, Lefkowitz RJ
    Switching of the coupling of the beta2-adrenergic receptor to different G proteins by protein kinase A. Nature 1997 Nov 6;390(6655):88-91
  13. Cao W, Luttrell LM, Medvedev AV, Pierce KL, Daniel KW, Dixon TM, Lefkowitz RJ, Collins S
    Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation. The Journal of biological chemistry 2000 Dec 8;275(49):38131-4
  14. Schmidt M, Evellin S, Weernink PA, von Dorp F, Rehmann H, Lomasney JW, Jakobs KH
    A new phospholipase-C-calcium signalling pathway mediated by cyclic AMP and a Rap GTPase. Nature cell biology 2001 Nov;3(11):1020-4
  15. Keiper M, Stope MB, Szatkowski D, Bohm A, Tysack K, Vom Dorp F, Saur O, Oude Weernink PA, Evellin S, Jakobs KH, Schmidt M
    Epac- and Ca2+ -controlled activation of Ras and extracellular signal-regulated kinases by Gs-coupled receptors. The Journal of biological chemistry 2004 Nov 5;279(45):46497-508
  16. Oestreich EA, Wang H, Malik S, Kaproth-Joslin KA, Blaxall BC, Kelley GG, Dirksen RT, Smrcka AV
    Epac-mediated activation of phospholipase C(epsilon) plays a critical role in beta-adrenergic receptor-dependent enhancement of Ca2+ mobilization in cardiac myocytes. The Journal of biological chemistry 2007 Feb 23;282(8):5488-95
  17. Pak Y, Pham N, Rotin D
    Direct binding of the beta1 adrenergic receptor to the cyclic AMP-dependent guanine nucleotide exchange factor CNrasGEF leads to Ras activation. Molecular and cellular biology 2002 Nov;22(22):7942-52
  18. Sato S, Fujita N, Tsuruo T
    Involvement of 3-phosphoinositide-dependent protein kinase-1 in the MEK/MAPK signal transduction pathway. The Journal of biological chemistry 2004 Aug 6;279(32):33759-67

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