Extracellular signal-regulated kinase cascades

Valjent, E., Corvol, J.C., Pages, C. et al. Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J. Neurosci. 20 8701, 2000. 

Pierce KL, Maudsley S, Daaka Y, Luttrell LM, Lefkowitz RJ (2000) Role of endocyto-sis in the activation of the extracellular signal-regulated kinase cascade by sequestering and nonsequestering G protein-coupled receptors. Proc Natl Acad Sd 97 1489-1494... 

Rubino T, Forlani G, Vigano D, Zippel R, Parolaro D (2004) Modulation of extracellular signal-regulated kinases cascade by chronic delta 9-tetrahydrocannabinol treatment. Mol Cell Neurosci 25 355-362... 

Berhow, M.T., Hiroi, N., Nestler, EJ. Regulation of ERK (extracellular signal regulated kinase), part of the neurotrophin signal transduction cascade, in the rat mesolimbic dopamine system by chronic exposure to morphine or cocaine. J. Neurosci. 16 4707, 1996. 

Figure 1 The MAPK pathway and its connections to other signals A negative feedback loop connects the phosphorylated endpoint of the pathway ERK (Extracellular-signal Regulated Kinase) to the transcriptionally-driven synthesis of the phosphatase, MKP MAP kinase phosphatase. MKP then de-phosphorylates ERK to shut down the signaling cascade. The positive feedback loop again starts with the terminal kinase ERK which activates cPLA2 (cytosolic phospholipase A2). This leads to the synthesis of arachidonic acid, which, in turn activates protein kinase C (PKC). PKC is a positive regulator of RAS (Please see Color Plate Section in the back of this book).

Coroneos, E., Wang, Y., Panuska, J.R., Temepleton, D.J. and Kester, M., 1996, Sphingohpid metabolites differentially regulate extracellular signal-regulated kinase and stress-activated protein kinase cascades, B/oclrem. J. 316 13-17. 

Pyne, S., Chapman, J., Steele, L. and Pyne, N.J., 1996, Sphingomyehn-derived lipids differentially regulate the extracellular signal-regulated kinase 2 (ERK-2) and c-Jun N-terminal kinase (JNK) signal cascades in airway smooth muscle. Ear. J. Biochem. 237 819-826. 

The TP receptor requires the G/G protein to activate the Src-Ras-ERKl/2 (extracellular signal-regulated kinase 1 and 2) cascade to induce the proliferative response, which in turn promotes the rapid nuclear translocation of activated ERKl/2 (201). Because TP receptor may be activated by many inflammatory mediators (202-204), these findings suggest new therapeutic strategies that alter the ASM hypertrophy or hyperplasia observed in the chronic airflow obstruction and airway inflammation that characterizes asthma, chronic bronchitis, bronchiolitis obliterans, and chronic obstructive pulmonary disease. 

Figure 3 The MARK cascade. A signaling cascade generally refers to a series of enzyme modification processes, as in the activation of extracellular signal-regulated kinase (Erk) isoforms, which are mammalian mitogen-activated protein kinases (MAPKs). The first kinase, Raf, is activated (indicated by an asterisk) by numerous inputs, allowing it to phosphorylate MEK on two sites Erk is phosphorylated dually in a similar fashion by MEK. Each phosphorylation event is thought to require a separate encounter between enzyme and substrate, which gives rise to interesting dynamical properties. Not depicted here, but equally important, are the phosphatases that catalyze the reverse reactions.

Agonist binding to opioid receptors also appears to activate the extracellular signal regulated kinase (ERK) cascade, which consists of three intracellular kinases a mitogen-activated protein kinase (MAPK)kinase kinase, a MAPK kinase, and a MAPK homolog (see Ref 100). This activation appears to be through Gj or Go (see Ref 100 and references cited therein). 

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