Article

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

ABSTRACT

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.

Download full-text

Full-text

Available from: Deborah K Morrison, Jun 30, 2015
  • Source
    • "Raf activates mitogen-activated protein (MAP) kinase, kinases 1 and 2 (MEK1/2), which in turn phosphorylates and activates the extracellular-signal-regulated kinases (ERK1 and ERK2). Activated ERKs phosphorylate and activate a vast array of substrates localized in all cellular compartments such as the RSK family (McCubrey et al., 2007; McKay and Morrison, 2007). Interestingly, TSC2 is repressed by the Ras/MAPK pathway in addition to its downregulation by the PI3K/Akt pathway, as evidenced by the observation that activated Erk1/2 directly phosphorylates TSC2 at sites that differ from the Akt target sites, thereby causing functional inactivation of the TSC1eTSC2 complex (Ma et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The phosphorylation of ribosomal protein S6 (rpS6) has been described for the first time about four decades ago. Since then, numerous studies have shown that this modification occurs in response to a wide variety of stimuli on five evolutionarily conserved serine residues. However, despite a large body of information on the respective kinases and the signal transduction pathways, the physiological role of rpS6 phosphorylation remained obscure until genetic manipulations were applied in both yeast and mammals in an attempt to block this modification. Thus, studies based on both mice and cultured cells subjected to disruption of the genes encoding rpS6 and the respective kinases, as well as the substitution of the phosphorylatable serine residues in rpS6, have laid the ground for the elucidation of the multiple roles of this protein and its posttranslational modification. This review focuses primarily on newly identified kinases that phosphorylate rpS6, pathways that transduce various signals into rpS6 phosphorylation, and the recently established physiological functions of this modification. It should be noted, however, that despite the significant progress made in the last decade, the molecular mechanism(s) underlying the diverse effects of rpS6 phosphorylation on cellular and organismal physiology are still poorly understood.
    Full-text · Chapter · Nov 2015
  • Source
    • "and migration, organ size control, and the hormone-regulated organogenesis (Stiles et al., 2004). The mitrogen-activated protein kinase (MAPK) /extracellular signal-regulated kinase (ERK) cascade is conserved in mammals and controls early developmental processes, including determination of morphology, organogenesis, synaptic plasticity and growth (McKay and Morrison, 2007). Signal transmission via this cascade is initiated by the activation of cell surface receptors by extracellular ligands, which results in the phosphorylation and activation of the MAPK/ERK kinases. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pten is a multifunctional tumor suppressor. Deletions and mutations in the Pten gene have been associated with multiple forms of human cancers. Pten is a central regulator of several signaling pathways that influences multiple cellular functions. One such function is in cell motility and migration, although the precise mechanism remains unknown. In this study, we deleted Pten in the embryonic lung epithelium using Gata5-cre mice. Absence of Pten blocked branching morphogenesis and ERK and AKT phosphorylation at E12.5. In an explant model, Pten(Δ/Δ) mesenchyme-free embryonic lung endoderm failed to branch. Inhibition of budding in Pten(Δ/Δ) explants was associated with major changes in cell migration, while cell proliferation was not affected. We further examined the role of ERK and AKT in branching morphogenesis by conditional, endodermal-specific mutants which blocked ERK or AKT phosphorylation. MEK(DM/+); Gata5-cre (blocking of ERK phosphorylation) lung showed more severe phenotype in branching morphogenesis. The inhibition of budding was also associated with disruption of cell migration. Thus, the mechanisms by which Pten is required for early endodermal morphogenesis may involve ERK, but not AKT, mediated cell migration.
    Preview · Article · Oct 2015 · Developmental Biology
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Insulin acts as the major regulator of the fasting-to-fed metabolic transition by altering substrate metabolism, promoting energy storage, and helping activate protein synthesis. In addition to its glucoregulatory and other metabolic properties, insulin can also act as a growth factor. The metabolic and mitogenic responses to insulin are regulated by divergent post-receptor signaling mechanisms downstream from the activated insulin receptor (IR). However, the anabolic and growth-promoting properties of insulin require tissue-specific inter-relationships between the two pathways, and the nature and scope of insulin-regulated processes vary greatly across tissues. Understanding the nuances of this interplay between metabolic and growth-regulating properties of insulin would have important implications for development of novel insulin and IR modulator therapies that stimulate insulin receptor activation in both pathway- and tissue-specific manners. This review will provide a unique perspective focusing on the roles of "metabolic" and "mitogenic" actions of insulin signaling in various tissues, and how these networks should be considered when evaluating selective pharmacologic approaches to prevent or treat metabolic disease. Copyright © 2015. Published by Elsevier Ireland Ltd.
    No preview · Article · Aug 2015 · Molecular and Cellular Endocrinology
Show more