Development - Beta-adrenergic receptors regulation of ERK

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].

References:

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