Ras-mitogen activated protein kinase

Pierce, R.C., Pierce-Bancroft, A.F., Prasad, B.M. Neurotrophin-3 contributes to the initiation of behavioral sensitization to cocaine by activating the Ras/Mitogen-activated protein kinase signal transduction cascade. J. Neurosci. 19 8685, 1999. 

In the proper cellular context in B cells, NK cells and mast cells, Syk kinase has been shown to transduce cell growth and survival signals by activating PI3K/Akt and Ras/mitogen-activated protein kinase pathways [3,46]. When deregulated, Syk activity can promote myelodysplasias, leukemogenesis, and perhaps viral-media ted cellular transformations [47,48]. By contrast, Syk has also been proposed to function as a tumor suppressor [49]. This is however, based on... 

Witta SE, Gemmill RM, Hirsch FR et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res 2006 66 944-950. Walker F, Kato A, Gonez LJ et al. Activation of the Ras/mitogen-activated protein kinase pathway by kinase-defective epidermal growth factor receptors results in cell survival but not proliferation. Mol Cell Biol 1998 18 7192-7204. 

Lopez, I., Mak, E.C., Ding, J., Hamm, H.E., and Lomasney, J.W., 2001, A novel bifunctional phospholipase C that is regulated by G([2 and stimulates the Ras/mitogen-activated protein kinase pathway. J. Biol. Chem. 276 2758-2765. 

Zhu Y, Hon T, Ye W, Zhang L. Heme deficiency interferes with the Ras-mitogen-activated protein kinase signaling pathway and expression of a subset of neuronal genes. Cell Growth Differ. 2002 13 431-439. 

In addition to PR-mediated transcriptional activities, progesterone also triggers intracellular phosphorylation cascades of the Src/Ras/mitogen-activated protein kinase pathway via PR [10, 11]. Also independent of the transcriptional activities of the receptor are rapid nongenomic effects of progesterone like modulation of sperm acrosome reaction [12], prevention of preterm labor [13] and Xenopus oocyte maturation [14]. 

Shyamala V, Khoja H. Interleukin-8 receptors R1 and R2 activate mitogen-activated protein kinases and induce c-fos, independent of Ras and Raf-1 in Chinese hamster ovary cells. Biochemistry 1998 37(45) 15918-15924. 

The Ras pathway is shown here. Ras is a G-protein that couples signaling from growth factors. The activated receptor is a GNRP that increases the exchange of GDP for GTP and activates the G-protein. Ras GAP inactivates the G-protein. The downstream signal for activated Ras is eventually the mitogen-activated protein kinase pathway (MAPK). 

FIGURE 2 0-5 Activation of PLC-e by heterotrimeric (Gal2/i3, GI(Vy, GJ and small G protein (Ras, Rho and Rap) signaling pathways (see text for details). (Modified with permission from reference [11].) Note that Ras, activated via the mitogen-activated protein kinase (MAPK) pathway, may also activate PLCe. For details of the MAPK pathways and abbreviations, see Chapter 24. 

The Farnesyl Group of H-Ras Facilitates the Activation of a Soluble Upstream Activator of Mitogen-activated Protein Kinase, P. McGeady, S. Kuroda, K. Shimizu, Y. Takai, M H. GelbJ. Biol Chem 1995,270,26347-26351. 

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).

Fig. 6. Role of signal transduction pathways in phosphorylating H3 at Ser-10 and Ser-28. The Ras-MAPK (mitogen activated protein kinase) pathway is activated by EGF (epidermal growth factor) and TPA (12-0-tetradecanoylphorbol-13-acetate). UV-B activates both the Ras-MAPK pathway and the p38 kinase pathway (for more information about the signal transduction pathways see http // kinase, oci.utoronto.ca/signallingmap.html).

The effects of insulin on transcription are shown on the left of the illustration. Adaptor proteins Crb-2 and SOS ( son of sevenless ) bind to the phosphorylated IRS (insulin-receptor substrate) and activate the G protein Ras (named after its gene, the oncogene ras see p.398). Ras activates the protein kinase Raf (another oncogene product). Raf sets in motion a phosphorylation cascade that leads via the kinases MEK and ERK (also known as MARK, mitogen-activated protein kinase ) to the phosphorylation of transcription factors in the nucleus. 

There are at least three major effector pathways that are activated by neurotrophic factor-Trk receptors. The best-characterized pathway is the extracellular-regulated kinase (ERK) cascade, which is regifiated by activation of Ras, a small membrane-bound G protein. Activation of Ras occurs when activated Trk receptor associates with adaptor proteins and a GTP exchange factor (see Russell and Duman 2002 for details). Ras in turn recruits and activates a serine threonine kinase, Raf, to the membrane resulting in the activation of ERK kinase (also referred to as MEK) and ERK (also known as mitogen activated protein kinase or MAPK). Activation of the Ras-Raf-MEK-ERK cascade can lead to regifiation of many celMar proteins, including ribosomal S6-kinase (RSK). 

The mitogenic activated protein kinase (MAPK) downstream from the Ras protein is organized in modules containing three types of protein kinases, which are successively activated by sequential phosphorylation events. The cell contains different MAPK modules, which differ in the nature of the triggering stimuli and the nature and specificity of the protein kinase components. The signal transducing function of a MAPK pathway is thus determined by the nature of the MAPK module involved this, in turn, depends on the properties of the protein kinases it contains, which differ in regulation and substrate specificity. The exact composition of the MAPK module is not fixed rather, different subtypes of protein kinase may be recruited to a module in a variable... 

Fig. 10.2. Components and activation of the ERK pathway. Ordering and specificity of protein kinases in the ERK pathway. ExtraceUular signals are registered via receptor tyrosine kinases and passed on to the Ras protein. Ras GTP activates protein kinases belonging to the group of MAPKK kinases (Raf kinases and MEEKs). The MAPKK kinases phosphorylate the downstream group of protein kinases, the MAPKKs at two Ser residues. The MAPKKs phosphorylate the MAPKs (ERKl and ERK2) at a Tyr and a Thr residue, and thus are classified as dual specificity kinases. MAPK mitogenic activated protein kinase ERK extracellularly regulated kinase MEK MAP/ERK kinase MAPKK MAPK kinase MAPKKK MAPKK kinase MEKK MEK kinase.

The SOS guanine-nucleotide exchange factor mediates GTP loading of Ras (Fig. 2), leading to activation of evolutionarily conserved effector proteins, such as the Raf ser-ine/threonine kinase, P13 K, and Ral-GDS. Raf activation triggers a cascade of phosphorylation events that lead to mitogen-activated protein kinase (MAPK) activation. 

---