Development - ACM2 and ACM4 activation of ERK

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ACM2 and ACM4 activation of ERK

ACM2 and ACM4 act via Guanine nucleotide binding proteins (G-protein) of G-protein alpha-i family. ACM2 can activate all representatives of the family and ACM4 acts exclusively via G-protein alpha-o and G-protein alpha-i2 [1]. A natural agonist of ACM2 and ACM4 is Acetylcholine.

ACM2 and ACM4 via G-protein beta/gamma released after transformation of G-protein alpha-i family activates PI3K cat class IB (p110-gamma)/ PtdIns(3,4,5)P3 / Shc/ GRB2/ SOS/ H-Ras/ c-Raf-1/ MEK2(MAP2K2) and MEK1(MAP2K1) cascade. MEK1(MAP2K1) and MEK2(MAP2K2) in turn activate ERK1/2 [2], [3].

In addition, ACM2 stimulates ERK1/2 activation in Protein kinase C (PKC) and/or Ca('2+)-dependent manner. Exactly mechanism this cascade is unknown. It may be realized via PLC-beta. PLC-beta produces IP3 and 1,2-Diacyglycerol . IP3 stimulates Ca('2+) releasing from endoplasmatic reticulum. Ca('2+) may activate Ca('2+) / Calmodulin/ CaMK II/ Pyk2(FAK2) [4], [5], [6].

In addition, 1,2-Diacyglycerol may participate in activation of PKC (e.g., PKC-alpha, PKC-delta or PKC-epsilon [7]), which may also stimulate Pyk2(FAK2).

It is known that ACM2 can transactivate EGFR via Fyn [8]. It is possible that Fyn is activated by Pyk2(FAK2), as it was shown for other receptors [9]. Fyn binds EGFR and probably leads to it's activation by autophosphorylation. Transactivated EGFR then leads to a common ERK pathway via Shc/ GRB2/ SOS/ H-Ras/ c-Raf-1/ MEK1(MAP2K1) and MEK2(MAP2K2)/ ERK1/2 [8].

Also, ACM2 activates Rap1GAP1 via G-protein alpha-i family, which prevents the inhibitory action of RAP-1A on c-Raf-1 and thereby promotes activation of ERK1/2 [10].

ACM2 and ACM4 dependent activation of ERK1/2 maintain Long-term potentiation of neurons [5] via p90RSK1 [11]/ CREB1/ EGR1 [12]. This also influences cell proliferation via p90RSK1 / CREB1/ c-Fos [13] and Elk-1 [5]. ACM2 activation of ERK participates in chemotactic cell migration [3] and in colon smooth muscle cell contraction via inhibitory phosphorylation of Caldesmon, which blocks Myosin ATPase [14].



Objects list:

1,2-Diacyglycerol 1,2-Diacyglycerol Compound group
ACM2 Muscarinic acetylcholine receptor M2
ACM4 Muscarinic acetylcholine receptor M4
Acetylcholine Chemical IUPAC name 2-acetyloxyethyl-trimethyl-ammonium
CREB1 Cyclic AMP-responsive element-binding protein 1
Ca('2+) Chemical IUPAC name calcium(+2) cation
Ca('2+) Chemical IUPAC name calcium(+2) cation
CaMK II CaMK II Complex
Caldesmon Caldesmon
Calmodulin Calmodulin
EGFR Epidermal growth factor receptor
EGR1 Early growth response protein 1
ERK1/2 Erk 1/2 Protein group
Elk-1 ETS domain-containing protein Elk-1
Fyn Tyrosine-protein kinase Fyn
G-protein alpha-i family G-protein alpha-i family Protein group
G-protein beta/gamma G-protein beta/gamma Group of complexes
GRB2 Growth factor receptor-bound protein 2
H-Ras GTPase HRas
IP3 Chemical IUPAC name [(1R,2S,3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-diphosphonooxycyclohexyl] dihydrogen phosphate
MEK1(MAP2K1) Dual specificity mitogen-activated protein kinase kinase 1
MEK2(MAP2K2) Dual specificity mitogen-activated protein kinase kinase 2
PI3K cat class IB (p110-gamma) Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform
PKC-alpha Protein kinase C alpha type
PKC-delta Protein kinase C delta type
PKC-epsilon Protein kinase C epsilon type
PLC-beta Phospholipase C, beta Protein group
PtdIns(3,4,5)P3 PtdIns(3,4,5)P3 Compound group
Pyk2(FAK2) Protein-tyrosine kinase 2-beta
RAP-1A Ras-related protein Rap-1A
Rap1GAP1 Rap1 GTPase-activating protein 1
SOS SOS Protein group
Shc SHC-transforming protein 1
c-Fos Proto-oncogene c-Fos
c-Raf-1 RAF proto-oncogene serine/threonine-protein kinase
p90RSK1 Ribosomal protein S6 kinase alpha-1

References:

  1. Migeon JC, Thomas SL, Nathanson NM
    Differential coupling of m2 and m4 muscarinic receptors to inhibition of adenylyl cyclase by Gi alpha and G(o)alpha subunits. The Journal of biological chemistry 1995 Jul 7;270(27):16070-4
  2. Lopez-Ilasaca M, Crespo P, Pellici PG, Gutkind JS, Wetzker R
    Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase gamma. Science (New York, N.Y.) 1997 Jan 17;275(5298):394-7
  3. Yamboliev IA, Wiesmann KM, Singer CA, Hedges JC, Gerthoffer WT
    Phosphatidylinositol 3-kinases regulate ERK and p38 MAP kinases in canine colonic smooth muscle. American journal of physiology. Cell physiology 2000 Aug;279(2):C352-60
  4. Wylie PG, Challiss RA, Blank JL
    Regulation of extracellular-signal regulated kinase and c-Jun N-terminal kinase by G-protein-linked muscarinic acetylcholine receptors. The Biochemical journal 1999 Mar 15;338 ( Pt 3):619-28
  5. Rosenblum K, Futter M, Jones M, Hulme EC, Bliss TV
    ERKI/II regulation by the muscarinic acetylcholine receptors in neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 2000 Feb 1;20(3):977-85
  6. Ma W, Maric D, Li BS, Hu Q, Andreadis JD, Grant GM, Liu QY, Shaffer KM, Chang YH, Zhang L, Pancrazio JJ, Pant HC, Stenger DA, Barker JL
    Acetylcholine stimulates cortical precursor cell proliferation in vitro via muscarinic receptor activation and MAP kinase phosphorylation. The European journal of neuroscience 2000 Apr;12(4):1227-40
  7. Raghunath A, Ling M, Larsson C
    The catalytic domain limits the translocation of protein kinase C alpha in response to increases in Ca2+ and diacylglycerol. The Biochemical journal 2003 Mar 15;370(Pt 3):901-12
  8. Stirnweiss J, Valkova C, Ziesche E, Drube S, Liebmann C
    Muscarinic M2 receptors mediate transactivation of EGF receptor through Fyn kinase and without matrix metalloproteases. Cellular signalling 2006 Aug;18(8):1338-49
  9. Qian D, Lev S, van Oers NS, Dikic I, Schlessinger J, Weiss A
    Tyrosine phosphorylation of Pyk2 is selectively regulated by Fyn during TCR signaling. The Journal of experimental medicine 1997 Apr 7;185(7):1253-9
  10. Mochizuki N, Ohba Y, Kiyokawa E, Kurata T, Murakami T, Ozaki T, Kitabatake A, Nagashima K, Matsuda M
    Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with G alpha(i) Nature 1999 Aug 26;400(6747):891-4
  11. Suzuki S, al-Noori S, Butt SA, Pham TA
    Regulation of the CREB signaling cascade in the visual cortex by visual experience and neuronal activity. The Journal of comparative neurology 2004 Nov 1;479(1):70-83
  12. Greenwood JM, Dragunow M
    Muscarinic receptor-mediated phosphorylation of cyclic AMP response element binding protein in human neuroblastoma cells. Journal of neurochemistry 2002 Jul;82(2):389-97
  13. Sun Y, Yamauchi J, Kaziro Y, Itoh H
    Activation of c-fos promoter by Gbetagamma-mediated signaling: involvement of Rho and c-Jun N-terminal kinase. Journal of biochemistry 1999 Mar;125(3):515-21
  14. Cook AK, Carty M, Singer CA, Yamboliev IA, Gerthoffer WT
    Coupling of M(2) muscarinic receptors to ERK MAP kinases and caldesmon phosphorylation in colonic smooth muscle. American journal of physiology. Gastrointestinal and liver physiology 2000 Mar;278(3):G429-37

  1. Migeon JC, Thomas SL, Nathanson NM
    Differential coupling of m2 and m4 muscarinic receptors to inhibition of adenylyl cyclase by Gi alpha and G(o)alpha subunits. The Journal of biological chemistry 1995 Jul 7;270(27):16070-4
  2. Lopez-Ilasaca M, Crespo P, Pellici PG, Gutkind JS, Wetzker R
    Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase gamma. Science (New York, N.Y.) 1997 Jan 17;275(5298):394-7
  3. Yamboliev IA, Wiesmann KM, Singer CA, Hedges JC, Gerthoffer WT
    Phosphatidylinositol 3-kinases regulate ERK and p38 MAP kinases in canine colonic smooth muscle. American journal of physiology. Cell physiology 2000 Aug;279(2):C352-60
  4. Wylie PG, Challiss RA, Blank JL
    Regulation of extracellular-signal regulated kinase and c-Jun N-terminal kinase by G-protein-linked muscarinic acetylcholine receptors. The Biochemical journal 1999 Mar 15;338 ( Pt 3):619-28
  5. Rosenblum K, Futter M, Jones M, Hulme EC, Bliss TV
    ERKI/II regulation by the muscarinic acetylcholine receptors in neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 2000 Feb 1;20(3):977-85
  6. Ma W, Maric D, Li BS, Hu Q, Andreadis JD, Grant GM, Liu QY, Shaffer KM, Chang YH, Zhang L, Pancrazio JJ, Pant HC, Stenger DA, Barker JL
    Acetylcholine stimulates cortical precursor cell proliferation in vitro via muscarinic receptor activation and MAP kinase phosphorylation. The European journal of neuroscience 2000 Apr;12(4):1227-40
  7. Raghunath A, Ling M, Larsson C
    The catalytic domain limits the translocation of protein kinase C alpha in response to increases in Ca2+ and diacylglycerol. The Biochemical journal 2003 Mar 15;370(Pt 3):901-12
  8. Stirnweiss J, Valkova C, Ziesche E, Drube S, Liebmann C
    Muscarinic M2 receptors mediate transactivation of EGF receptor through Fyn kinase and without matrix metalloproteases. Cellular signalling 2006 Aug;18(8):1338-49
  9. Qian D, Lev S, van Oers NS, Dikic I, Schlessinger J, Weiss A
    Tyrosine phosphorylation of Pyk2 is selectively regulated by Fyn during TCR signaling. The Journal of experimental medicine 1997 Apr 7;185(7):1253-9
  10. Mochizuki N, Ohba Y, Kiyokawa E, Kurata T, Murakami T, Ozaki T, Kitabatake A, Nagashima K, Matsuda M
    Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with G alpha(i) Nature 1999 Aug 26;400(6747):891-4
  11. Suzuki S, al-Noori S, Butt SA, Pham TA
    Regulation of the CREB signaling cascade in the visual cortex by visual experience and neuronal activity. The Journal of comparative neurology 2004 Nov 1;479(1):70-83
  12. Greenwood JM, Dragunow M
    Muscarinic receptor-mediated phosphorylation of cyclic AMP response element binding protein in human neuroblastoma cells. Journal of neurochemistry 2002 Jul;82(2):389-97
  13. Sun Y, Yamauchi J, Kaziro Y, Itoh H
    Activation of c-fos promoter by Gbetagamma-mediated signaling: involvement of Rho and c-Jun N-terminal kinase. Journal of biochemistry 1999 Mar;125(3):515-21
  14. Cook AK, Carty M, Singer CA, Yamboliev IA, Gerthoffer WT
    Coupling of M(2) muscarinic receptors to ERK MAP kinases and caldesmon phosphorylation in colonic smooth muscle. American journal of physiology. Gastrointestinal and liver physiology 2000 Mar;278(3):G429-37

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