Pathway Map Details

Development_ACM2 and ACM4 activation of ERK

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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,, Ca('2+) = Ca('2+), PLC-beta, PKC-delta, Elk-1, G-protein alpha-i2,, 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)


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].


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