Pathway maps

Development_Beta-adrenergic receptors regulation of ERK
Development_Beta-adrenergic receptors regulation of ERK

Object List (links open in MetaCore):

SOS, PKA-cat alpha, cAMP, RAP-2B, RAP-1A, PI3K reg class IB (p101), PKA-cat (cAMP-dependent), PtdIns(3,4,5)P3, DAG, c-Raf-1, H-Ras, PDK (PDPK1), G-protein beta/gamma, PDZ-GEF1, ATP, PP2A catalytic, Beta-2 adrenergic receptor, Beta-1 adrenergic receptor, Noradrenaline, Adenylate cyclase, IP3, <endoplasmic reticulum lumen> Ca('2+) = <cytosol> Ca('2+), cAMP-GEFI, Shc, B-Raf,, GRB2, PKA-reg (cAMP-dependent), G-protein alpha-i family, c-Src, CalDAG-GEFII, MEK2(MAP2K2), IP3 receptor, Beta-3 adrenergic receptor, PLC-epsilon, Ca('2) cytosol, CD44, c-Jun,, G-protein alpha-s, PtdIns(4,5)P2, PI3K cat class IB (p110-gamma),, Erk (MAPK1/3), Adrenaline, MEK1(MAP2K1), Ca('2+) endoplasmic reticulum lumen


Beta-adrenergic receptor-induced regulation of ERK

Beta-1, Beta-2 and Beta-3 adrenergic receptors can activate Mitogen-activated protein kinase 1 and 3 ( Erk (MAPK1/3) ) phosphorylation in v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras ) - dependent and independent manner with various physiological effects, such as cardiomyocytes hypertrophy [1], cell growth and development [2], proliferation [3], cell migration [4], and long-term potentiation in neurons [5].

For example, Beta-2 adrenergic receptor activate GNAS complex locus ( G-protein alpha-s )/ Adenylate cyclases, which leads to Adenosine 3',5'-cyclic phosphate ( cAMP ) production. This activates Protein kinase cAMP-dependent regulatory ( PKA-reg (cAMP-dependent) and catalytic ( PKA-cat (cAMP-dependent) ) subunits. PKA-cat activates RAP1A member of RAS oncogene family ( RAP-1A )/ v-raf murine sarcoma viral oncogene homolog B1 ( B-Raf )/ Mitogen-activated protein kinase kinase 2 and 1 ( MEK2(MAP2K2) and MEK1(MAP2K1) )/ Erk [6]. In addition, Beta adrenergic receptor -dependent cytosolic redistribution of RAP-1A may participate, for example, in parotid gland secretion [7]. It is shown, that PKA -activated Erk takes part in cardiomyocytes hypertrophy in normal and pathological processes [1].

It is also known that cAMP levels may be regulated via beta-arrestin-dependent signaling [8].

In addition, Beta adrenergic receptor may inhibit Erk (stimulated by Beta adrenergic or other receptors), possibly, via PKA/ v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ) cascade [9], [10], [11].

PKA-cat phosphorylation of Beta-2 adrenergic receptor leads to its activation switch from G-protein alpha-i family to G-protein alpha-s. G-protein alpha-i family activation releases complex of G-protein beta/gamma, which activates c-src tyrosine kinase ( c-Src ) [12]. Moreover, Beta-3 adrenergic receptor can activate c-Src directly [13]. c-Src phosphorylates SHC transforming protein 1 ( Shc ) and Growth factor receptor-bound protein 2 ( GRB2 ), activating Son of sevenless homolog ( SOS )/ H-Ras/ c-Raf-1 and subsequent MEK and Erk activation [12], [13].

Additionally, cAMP activates Erk in PKA- independent manner via Rap guanine nucleotide exchange factor 3 ( cAMP-GEFI )/ RAP2B member of RAS oncogene family ( RAP-2B ) or RAP-1A/ Phospholipase C epsilon 1 ( PLC-epsilon ) [14], [15], [16]. PLC-epsilon catalyzes transformation of Phosphatidylinositol-4,5-bisphosphate ( PtdIns(4,5)P2 ) to 1,2-diacyl-glycerol ( DAG ) and Inositol 1,4,5-trisphosphate ( IP3 ). IP3 activates Inositol 1,4,5-triphosphate receptor type 3 ( IP3 receptor )-mediated Ca('2+) release from endoplasmic reticulum [14], [15]. Ca('2+) and DAG activate RAS guanyl releasing protein 1 ( CalDAG-GEFII ), which triggers H-Ras/ c-Raf-1/ MEK/ Erk activation [15]. It has been shown that cAMP-GEFI -activated Erk may participate in cell growth and development via adhesion molecule CD44 in salivary gland cells [2].

Beta-1 adrenergic receptor may also stimulate Rap guanine nucleotide exchange factor (GEF) 2 ( PDZ-GEF1 ) directly and/or via cAMP. PDZ-GEF1/ H-Ras cascade leads to Erk activation [17].

Beta-2 adrenergic receptor may activate adult cell proliferation via some Phosphoinositide-3-kinase ( PI3K )-dependent pathway, possibly G-protein beta/gamma/ PI3K/ PtdIns(3,4,5)P3/ 3-phosphoinositide dependent protein kinase-1 ( PDK (PDPK1) )/ MEK/ Erk cascade [3], [18].

Beta-2 adrenergic receptor may inhibit migration of keratinocyte via G-protein alpha-s/ cAMP -dependent activation of Protein phosphatase 2 ( PP2A ), which inhibits Epidermal growth factor receptor ( EGFR )-transactivated Erk [4].


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