Pathway maps

Development_Activation of ERK by Alpha-1 adrenergic receptors
Development_Activation of ERK by Alpha-1 adrenergic receptors

Object List (links open in MetaCore):

PI3K cat class IA (p110-beta), G-protein alpha-0, PKC-epsilon, PLC-beta1, PI3K reg class IA (p85-alpha), SOS1, c-Raf-1,, PKC-delta, PKC-alpha, CaMK II, Ca('2) cytosol, TGM2, Ca('2+) endoplasmic reticulum, G-protein alpha-q, MEK1(MAP2K1),, MEK2(MAP2K2), Alpha-1A adrenergic receptor, c-Src, IP3, Noradrenaline extracellular region, PLC-delta 1, H-Ras, c-Fos, Adrenaline extracellular region, IP3 receptor, G-protein alpha-14, G-protein beta/gamma, L-type Ca(II) channel, alpha 1C subunit, PtdIns(3,4,5)P3, PtdIns(4,5)P2, G-protein alpha-11, Alpha-1B adrenergic receptor, Shc, G-protein alpha-15, c-Jun, Pyk2(FAK2), Erk (MAPK1/3), Alpha-1D adrenergic receptor, DAG, Ca('2+) extracellular region, None, None, Calmodulin


Activation of ERK by Alpha-1 adrenergic receptors

Subtype alpha-1 adrenergic receptors consists of Alpha-1A adrenergic receptor, Alpha-1B adrenergic receptor and Alpha-1D adrenergic receptor. They participate in many physiological processes via different pathways. One of the best studied alpha-1 adrenergic receptors-stimulated pathways is a Mitogen-activated protein kinase 1 and 3 ( ERK1/2 ) activation [1], [2].

Natural catecholamines, Adrenaline, and Noradrenaline, activate alpha-1 adrenergic receptors [1], [3]. The activated receptors interact with different Guanine nucleotide binding proteins (G-proteins). All three receptors interact with G-protein alpha-q and G-protein alpha-11 [4]. Alpha-1A adrenergic receptor and Alpha-1B adrenergic receptor couple with G-protein alpha-14 [5]. Alpha-1B adrenergic receptor and Alpha-1D adrenergic receptor interact with Transglutaminase 2 ( TGM2 ) [6], [7], [8]. Alpha-1B adrenergic receptor couples with G-protein alpha-15 [5] and G-protein alpha activating activity polypeptide O ( G-protein alpha-o ) [4].

G-protein alpha-11, G-protein alpha-q, G-protein alpha-14, G-protein alpha-15 activate Phospholipase C beta 1 ( PLC-beta1 ) [5], [1], [9]. TGM2 activate Phospholipase C delta 1 ( PLC-delta1 ) [10], [8]. PLC-beta1 and PLC-delta1 hydrolyze Phosphatidylinositol-4,5-bisphosphate ( PtdIns(4,5)P2 ) to produce Inositol 1,4,5-trisphosphate ( IP3 ) and 1,2-diacyl-glycerol ( DAG ) [11], [8].

DAG and IP3 participate in activation of Ca('2+) -dependent Protein kinase C alpha ( PKC-alpha ) [12], Ca('2+) -independent Protein kinases C delta and epsilon ( PKC-delta and PKC-epsilon ) [13], [1], [14] and mobilization of intracellular Ca('2+). All these pathways may lead to activation of cell growth and proliferation.

Cytosolic Ca('2+) activates Calmodulin/ Calcium/calmodulin-dependent protein kinase II ( CaMK II )/ PTK2B protein tyrosine kinase 2 beta ( Pyk2(FAK2) )/ v-src sarcoma viral oncogene homolog ( c-Src )/ SHC transforming protein ( Shc )/ 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 kinases 1 and 2 (( MEK1(MAP2K1) and MEK2(MAP2K2) )/ Mitogen-activated protein kinase 1 and 3 ( ERK1/2 ) pathway [15], [13].

G-protein alpha-q -stimulated PKC-alpha and PKC-epsilon may activate Erk cascade in H-Ras -independent manner (e.g., via phosphorylation of c-Raf-1) [16], [17]. On the other hand PKC-delta and PKC-epsilon may activate Erk cascade in H-Ras -independent manner via phosphorylation of Pyk2(FAK2) [16], [18], [19].

Alpha-1 adrenergic receptors-dependent ERK1/2 activation may also be realized via Phosphoinositide-3-kinase ( PI3K ) [20], [21]. c-Src can activate PI3K reg class IA (p85-alpha)/ PI3K cat class IA (p110-beta) directly [21], [22], [23] or via SHC transforming protein ( Shc )/ Son of sevenless homolog ( SOS )/ H-Ras [21].

Activated PI3K catalyzes transformation of PtdIns(4,5)P2 in to Phosphatidylinositol-3,4,5-trisphosphate ( PtdIns(3,4,5)P3 ). Presumably, then PtdIns(3,4,5)P3 activates Shc/ SOS/ H-Ras. After that, H-Ras activates c-Raf-1/ MEK1(MAP2K1), MEK2(MAP2K2) )/ ERK1/2 [20], [15], [21].

Activated ERK1/2 phosphorylate V-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) and Jun oncogene ( c-Jun ), thus activating cell growth and proliferation [21], [13], [1].

Moreover, PKC-alpha, probably phosphorylates Ca2+ channels (for example, Calcium channel, voltage-dependent L type ( L-type Ca(II) channel ) [24], [25] ) and this increase extracellular Ca('2+) entry [26]. High level of Ca('2+) influence cell contraction [2]. Also, high level of Ca('2+), which was achieved due Ca2+ channels activation, may facilitate activation of Ca('2+) -dependent PKC-alpha, thus creating a positive feedback loop. CaMK II may activates L-type Ca(II) channel as well [27].


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