Integrating signals from RTKs to ERK/MAPK. Oncogene

Laboratory of Cell and Developmental Signaling, NCI-Frederick, Frederick, MD 21702, USA.
Oncogene (Impact Factor: 8.46). 06/2007; 26(22):3113-21. DOI: 10.1038/sj.onc.1210394
Source: PubMed


Signals received at the cell surface must be properly transmitted to critical targets within the cell to achieve the appropriate biological response. This process of signal transduction is often initiated by receptor tyrosine kinases (RTKs), which function as entry points for many extracellular cues and play a critical role in recruiting the intracellular signaling cascades that orchestrate a particular response. Essential for most RTK-mediated signaling is the engagement and activation of the mitogen-activated protein kinase (MAPK) cascade comprised of the Raf, MEK and extracellular signal-regulated kinase (ERK) kinases. For many years, it was thought that signaling from RTKs to ERK occurred only at the plasma membrane and was mediated by a simple, linear Ras-dependent pathway. However, the limitation of this model became apparent with the discovery that Ras and ERK can be activated at various intracellular compartments, and that RTKs can modulate Ras/ERK signaling from these sites. Moreover, ERK scaffolding proteins and signaling modulators have been identified that play critical roles in determining the strength, duration and location of RTK-mediated ERK signaling. Together, these factors contribute to the diversity of biological responses generated by RTK signaling.

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Available from: Deborah K Morrison, Jun 30, 2015
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    • "In conditions where insulin levels are elevated, signaling through the IR can activate mitogenic pathways (Bedinger et al., 2015, Jensen et al., 2007, Vigneri et al., 2009, Entingh-Pearsall and Kahn, 2004). Phosphorylated IR and IRS-1 are bound by the Shc protein where they serve as effective adapters for the GRB2-SOS complex, thus activating RAS and the mitogen activated protein kinase (MAPK) cascade (Hansen et al., 1996, Ceresa and Pessin, 1998, McKay and Morrison, 2007). The activated MAPK, extracellular signal-regulated kinase (ERK1/2, also referred to as p44/p42 MAPK), is a key regulator of the mitogenic response to insulin and the IGFs (Johnson and Lapadat, 2002). "
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    Molecular and Cellular Endocrinology 08/2015; 415. DOI:10.1016/j.mce.2015.08.013 · 4.41 Impact Factor
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    • "This signaling includes pathways and pathwayimmanent target molecules which direct cell behavioral aspects such as proliferation, differentiation and motility. Several routes of activation have been described for MAP-kinases and p190RhoGAP in the context of GFRs [20] and FAs [45] [46]. Moreover, MAP-kinase signaling and p190RhoGAP phosphorylation were also shown to emerge from Src [47] [48]. "
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    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 06/2015; DOI:10.1016/j.bbamcr.2015.06.004 · 5.02 Impact Factor
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    • "These included primarily transcription and translational machinery (Structural constituent of ribosome, rRNA binding, Transcription regulatory region sequence-specific DNA binding), cell signaling components (GTP binding, GTPase mediated signal transduction, postsynaptic membrane, cell junction, G-protein coupled receptor signaling, outer membrane-bound periplasmic space, MAPK cascade, regulation of ion transmembrane transport) and ATP coupled proton transport (ATP hydrolysis coupled proton transport, ATP synthesis coupled proton transport, proton-transporting V-type ATPase). Of particular interest were the four GO terms for which all members were present in the enriched set only (i.e., the GO term constituents contained only synonymous substitutions; Table S13): (1) outer-membrane bound periplasmic space (GO0030288) contained glutamate receptors responsible for postsynaptic excitation of insect neuronal and muscle cells (Briley et al., 1981), (2) the MAPK cascade (GO0000165) that communicates biotic and abiotic signals from extracellular ligands to the nucleus, initiating a response (e.g., division, apoptosis, etc.) from the cell (McKay & Morrison, 2007), (3) proton-transporting V-type ATPases (GO0033180) that are a diverse and highly conserved membrane-spanning enzyme coupling ATP hydrolysis to proton transport (Nelson et al., 2000), and (4) the transcription regulatory region sequence-specific DNA binding ontology (GO0000976) that contains several homeobox domains encoding transcription factors which activate and regulate patterns of morphogenesis (Gehring, 1992). "
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