Development - ACM2 and ACM4 activation of ERK

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].

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References:

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