MAP Kinase Cascades

The duration of signaling influences how a cell responds to a particular stimulus. For example, brief activation of the MAP kinase cascade in the neuronal cell line, PCI 2, results in proliferation, while sustained... 

Immune Defense JAK-STAT Pathway PIAS proteins Map Kinase Cascades Toll-like Receptors Growth Factors... 

Stimulation of the insulin receptor results in the activation of two major pathways [3] (i) the mitogen-activated protein (MAP) kinase cascade (discussed in chapter MAP kinase cascade) and (ii) the phospha-tidylinositol 3-kinase (PI 3-kinase) pathway which has been extensively studied in the context of the metabolic responses to insulin (summarized in Table 1 and Fig. 2). 

MAP Kinase Cascades. Figure 1 Organization of MAPK cascades. See text for details. 

MAP Kinase Cascades. Table 1 Pharmacological Inhibitors of MAPK Cascades... 

Mitogen activated protein kinase. MAP Kinase Cascade... 

The classical PTPs can be subdivided into receptorlike PTPs and nonreceptor, cytosolic PTPs. The second category of PTPs are broadly defined as dual specificity phosphatases (DSPs), which dephosphorylate pSer/ pThr as well as pTyr. MAP kinase phosphatases (MKPs) ( MAP kinase cascades) and PTEN are examples of DSP family members. Remarkably, PTEN also has lipid phosphatase activity that is specific for phosphatidylinositol-3,4,5-trisphosphate generated in response to the actions of PI3K. Finally, the class of low molecular mass (LM-) PTPs and that of CDC25 PTPs accomplish the cells repertoire of PTPs (Fig. 3). 

Activated Ras triggers signalling down the Raf-MEKl / 2-Erkl/2-RSKl MAP kinase cascade. This process is inhibited by the RasGAP neurofibromin (NF1). Both Erkl/and RSK1 can directly phosphorylate TSC2 and these phosphorylation events inhibit the GAP activity of TSC2 and thus ultimately promote mTORCl activity. 

Ludwig S (2007) Influenza viruses and MAP kinase cascades - novel targets for antiviral intervention, Signal Transduction 7 81-88... 

Sugden PH, Clerk A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors. Cell Signal 1997 9(5) 337—351. 

Treisman, R., Regulation of transcription by MAP kinase cascades, Curr. Opin. Cell. Biol., 8, 205-215, 1996. 

F. Galbiati, D. Volonte, J. A. Engelman, G. Watanabe, R. Burke, R. G. Pestell, and M. P. Lisanti. Targeted downregulation of caveolin-1 is sufficient to drive cell transformation hyperactivate the p42/44 MAP kinase cascades. EMBO J. 17 6633-6648 (1998). 

Thomson S, Clayton AL, Hazzalin CA, Rose S, Barratt MJ, Mahadevan LC (1999) The nucleosomal response associated with immediate-early gene induction is mediated via alternative MAP kinase cascades MSKl as a potential histone H3/HMG-14 kinase. Embo J 18(17) 4779-4793 Trivier E, De Cesare D, Jacquot S, Pannetier S, Zackai E, Young I, Mandel JL, Sassone-Corsi P, Hanauer A (1996) Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384(6609) 567-570... 

Figure 21.9 The mitogen-activated protein kinase cascade (MAP kinase cascade). The active protein Ras activates Raf by promoting its recruitment to a cell membrane. Through a series of phosphorylations MAP kinase is activated as follows MAP kinase kinase kinase (Raf) phosphorylates MAP kinase kinase which, in turn, phosphorylates MAP kinase, the final target enzyme. MAP kinase phosphorylates transcription factors for genes that express proteins involved in proliferation. Another nomenclature for the enzymes is also used raf is MEKK MAPKK is MEK and finally ERK is MAP kinase (ERK is the abbreviation for extracellular-signal-related kinase) For comparison, the reader is referred to the metabolic phosphorylase cascade, which is discussed in Chapter 12 (Figure 12.12).

Role of membrane attachments The Ras-stimulated cascade depends on the binding of components of the cascade to the cell membrane. Ras itself is attached to the plasma membrane and it activates Raf (the first enzyme in the MAP kinase cascade) by causing it to bind to the membrane. 

Carter S, Auer KL, Reardon DB, et al. Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells. Oncogene 1998 16 2787-2796. 

Sweat J (2001) The nem-onal MAP kinase cascade a biochemical signal integration system subserving synaptic plasticity and memory. J Neurochem 76 1-10 Szapiro G, Vianna MRM, McGaugh JL, Medina JH, Izquierdo 1 (2003) The role of NMDA glutamate receptors, PKA, MAPK, and CAMKll in the hippocampus in extinction of conditioned fear. Hippocampus 13 53-58... 

Maeda, T. Wurgler-Murphy, S.M. Saito, H. A two-component system that regulates an osmosensing MAP kinase cascade in yeast. Nature, 369, 242-245 (1994)... 

Phosphorylated IRS-1 activates a second signaling pathway by interacting with an 85-kDa SH2-containing protein that is a subunit of phophatidylinositol 3-kinase.384 386 This activates the 110-kDa catalytic subunit of the 3-kinase, which catalyzes formation of phosphatidylinositol 3-phosphate as well as Ptdlns (3,4)P2 and Ptdlns (3,4,5)P3.387/387a These compounds, which remain within membranes, activate other branches of the signaling cascade, some of which may converge with those of the MAP kinase cascade. However, there appears to be specific activation of a ribosomal Ser/Thr kinase that, among other activities, phosphorylates ribosomal protein S6, a component of the small ribosomal subunit.388 It also phosphorylates some isoforms of protein kinase C and other enzymes. Ptdlns 3-kinase may also activate 6-phosphofructo-2-kinase (Fig. 11-2, step ti).384/388... 

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