Pathway maps

Development_ACM2 and ACM4 activation of ERK
Development_ACM2 and ACM4 activation of ERK

Object List (links open in MetaCore):

H-Ras, GRB2, ERK1/2, CaMK II, Shc, MEK2(MAP2K2), Calmodulin, Ca('2+) endoplasmic reticulum lumen, c-Raf-1, c-Fos, DAG, EGFR, p90RSK1, EGR1, CREB1, PtdIns(4,5)P2, ACM2, Fyn, Rap1GAP1, IP3, PtdIns(3,4,5)P3, SOS, 2.7.1.153, <endoplasmic reticulum lumen> Ca('2+) = <cytosol> Ca('2+), PLC-beta, PKC-delta, Elk-1, G-protein alpha-i2, 3.1.4.11, Caldesmon, ACM4, G-protein alpha-o, MEK1(MAP2K1), RAP-1A, Ca('2) cytosol, G-protein alpha-i family, Pyk2(FAK2), IP3 receptor, PKC-alpha, acetylcholine, PKC-epsilon, G-protein beta/gamma, PI3K cat class IB (p110-gamma)

Description

ACM2 and ACM4 activation of ERK

Cholinergic receptor muscarinic 2 and 4 ( 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 Phosphoinositide-3-kinase catalytic gamma polypeptide ( PI3K cat class IB (p110-gamma) )/ Phosphatidylinositol-3,4,5-trisphosphate ( PtdIns(3,4,5)P3 )/ 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 2 and 1 ( MEK2 and MEK1 ) cascade. MEK1 and 2 in turn activate Mitogen-activated protein kinase 1 and 3 ( 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 Phospholipase C beta ( PLC-beta ). PLC-beta produces Inositol 1,4,5-trisphosphate ( IP3 ) and 1,2-diacyl-glycerol ( DAG ). IP3 stimulates Ca('2) releasing from endoplasmatic reticulum. Ca('2) cytosol may activate Ca('2) cytosol/ Calmodulin/ Calcium/calmodulin-dependent protein kinase II ( CaMK II )/ PTK2B protein tyrosine kinase 2 beta ( Pyk2(FAK2) ) [4], [5], [6].

In addition, DAG 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 Epidermal growth factor receptor ( EGFR ) via FYN oncogene related to SRC FGR and YES ( Fyn ) [8]. It is possible that Fyn is activated by Pyk2(FAK2), as it was shown for other receptors [9]. Fyn binds Epidermal growth factor receptor ( 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 and 2/ ERK1/2 [8].

Also, ACM2 activates RAP1 GTPase activating protein ( Rap1GAP1 ) via G-protein alpha-i family, which prevents the inhibitory action of RAP1A member of RAS oncogene family ( RAP-1A ) on c-Raf-1 and thereby promotes activation of ERK1/2 [10].

ACM2 and ACM4 dependent activation of ERK 1/2 maintain Long-term potentiation of neurons [5] via Ribosomal protein S6 kinase 90kDa polypeptide 1 ( p90RSK1 ) [11]/ cAMP responsive element binding protein 1 ( CREB1 )/ Early growth response 1 ( EGR1 ) [12]. This also influences cell proliferation via p90RSK1/ CREB1/ v-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) [13] and ELK1 member of ETS oncogene family ( 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].

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