Mar 16, 2022 · Kinase activation occurs in the RTK signaling pathway. Ras causes phosphorylation of ser/thr, which activates MAP kinase. This kinase enters the nucleus and activates transcription factors, resulting in various cellular responses. However, in the GPCR pathway, cAMP-dependent proteins activate protein kinase C.
Aug 01, 2007 · RAS was shown to activate RAF following growth factor induction of NIH 3T3 cells and NGF induction of PC12 cells and this activation was blocked with a dominant-negative RAS (M17 RAS ). (3) Protein kinase Cα (PKCα), which is being activated at the plasma membrane was observed to phosphorylate RAF [108] .
Apr 12, 2017 · levels of Ras activity, provided by the RasD38E mutant, rescue R8 differentiation and survival but not R1-R7 differentiation. High levels of Ras/MAPK activity provided by wild-type Ras or by a combination of RasD38E and rlSem are required for the differentiation of R1-R7 photoreceptor cells. There are two possibilities with regard to the nature ...
Monomeric G protein (similar to alpha subunit on trimeric), GTPase superfamily, lipid-anchored protein Downstream effector of RTK signaling Similar to Ga but smaller, low GTPase activity, is not linked directly to cell-surface receptors When bound to GDP – inactive Bound to GTP – active Ras activity is regulated by GEFs and GAPs o Can be ...
RAS proteins are small GTPases, which serve as master regulators of a myriad of signaling cascades involved in highly diverse cellular processes . RAS oncogenes have been originally discovered as retroviral oncogenes, and ever since constitutively activating RAS mutations have been identified in human tumors, they are in the focus ...
As mentioned above, the activity of RAS proteins is tightly controlled by switching between the GDP- and GTP-bound states. Although RAS proteins possess intrinsic GTP-ase activity, regulatory proteins like guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) profoundly influence the activation of RAS. As the cellular amount of GTP is tenfold higher than GDP, GEFs promote the formation of active GTP–RAS, while GAPs stimulate the intrinsic rate of GTP hydrolysis and thereby the formation of GDP-RAS. Oncogenic RAS mutations at residues G12, G13 and Q61 render them constitutively active (GTP–RAS) as they are impaired in their intrinsic and GAP-mediated GTP hydrolysis. Three main classes of RAS GEFs are currently known with a common CDC25 homology catalytic domain and an N-terminal RAS exchange motif: SOS, RAS-GRF and RAS-GRP. SOS and RAS-GRF also serve as GEFs for Rac GTPases.
The first cellular RAS oncogene was cloned in 1982 and recently the Beatson Institute for Cancer Research in Glasgow, UK has successfully organized a wonderful meeting on RAS signaling and cancer to commemorate 24 years of intense RAS research. There is an old saying that “familiarity breeds contempt”, which is however not true in the context of RAS research. The field has grown tremendously in the past years with more than 150 family members and as many as 10 effector pathways have been identified so far for RAS alone. The functional interplay of many of these effector pathways needs to be worked out in future in more detail. Apart from the effector cascades identified, the RAF/MEK/ERK pathway as well as the PI3K pathway still happened to be the most valuable targets for cancer therapy. The recent identification of RalGEFs as crucial regulators of human cell transformation has opened up a new window in the search for new targets for therapeutic intervention. The use of large-scale RNA interference libraries shows considerable promise in quickly uncovering the crucial components of RAS induced signaling cascades. The recent discovery that RAS oncogene expression is modulated by microRNAs has added a new facet to RAS research. In the days to come, microRNAs regulating other downstream targets of the RAS signaling cascades will be deciphered as well. There is no doubt that these studies will keep up the momentum and excitement of this ever growing field of RAS biology, thereby retaining RAS at the heart of cancer research for the next decades. Finally it is befitting to quote the concluding lines from Robert Frost's famous poem:#N#The woods are lovely, dark, and deep, But I have promises to keep, And miles to go before I sleep, And miles to go before I sleep.
Though both receptors activate RAS, the timing of RAS/MAPK activation with both the receptors was different. While treatment with EGF leads to a transient activation of ERK, treatment with NGF caused a sustained RAS/MAPK activation leading to differentiation of these cells.
RAS proteins control cellular signaling pathways responsible for growth, migration, adhesion, cytoskeletal integrity, survival and differentiation. RAS proteins belong to the large family of small GTPases, which are activated in response to various extracellular stimuli.
p120 GAP was the first identified member of the GAP family. In addition to the catalytic domain, this protein also harbors SH2, SH3 and PH domains and phospholipid binding motifs. RAS–GAP was the first protein found to interact with the so-called effector domain of RAS [76]. Consequently, RAS–GAP was originally perceived as a major RAS signal terminator. Indeed, initial evidence suggested that RAS–GAP is in a complex with receptor and non-receptor tyrosine kinases [77], [78]. However, in contrast to GEFs, there are only a few details known with respect to pathways modulating RAS–GAP activity. Yang et al. demonstrated that the partial cleavage of RAS–GAP by caspase-3 is required to activate AKT leading to cell survival under mild stress conditions [79]. Neurofibromin, another RAS–GAP, acts as a tumor suppressor gene and it is lost in the autosomal dominantly inherited disorder neurofibromatosis type 1 (NF1). Intracellular levels of neurofibromin have been shown to be dynamically regulated by the ubiquitin–proteasome pathway [80]. Degradation is rapidly triggered in response to growth factors and requires sequences adjacent to the catalytic GAP-related domain of neurofibromin. However, whereas degradation is rapid, neurofibromin levels are re-elevated shortly after growth factor treatment. Accordingly, NF1 -deficient mouse embryonic fibroblasts exhibit an enhanced activation of RAS, prolonged RAS and ERK activities, and proliferate in response to sub-threshold levels of growth factors. Recent evidence suggests a crucial role for NF1 in the activation of mTOR, an evolutionarily conserved serine/threonine protein kinase that regulates cell growth and proliferation in yeast, flies, and mammals. mTOR is constitutively activated in cells derived from NF1-deficient mice and this aberrant activation depends on the phosphorylation of tuberin by activated AKT [81]. Additional RAS–GAPs have been identified and their mode of activation has been characterized. The Ca 2+ -promoted RAS inactivator CAPRI was identified as a RAS–GAP stimulated by elevated intracellular Ca 2+ levels leading to attenuation of RAS activation and MAPK activity [82]. Another member of the GAP1 family responding to Ca 2+ spikes is RAS GTPase-activating-like RASAL, which is highly expressed in follicular cells of the thyroid and the adrenal medulla [83]. RASAL oscillates between the cytosol and the plasma membrane in response to Ca 2+ spikes thereby decoding the complex Ca 2+ oscillations into a dynamic regulation in the activation of RAS [84].
RAS effectors are defined as proteins with a strong affinity to GTP–RAS, whose binding is impaired by mutations within the core effector domain. The binding of RAS effector proteins to GTP–RAS triggers distinct signaling cascades. However, the notion that GDP–RAS does not have any functional role has been challenged by the recent observation that GDP–RAS indeed interacts with several effector proteins and modulates downstream signaling events. For instance, GDP–RAS binds to the transcription factor Aiolos, thereby modulating the nuclear translocation of Aiolos and the expression of anti-apoptotic protein BCL-2 [95], [96]. In 1993, RAF kinase was first discovered as a RAS effector followed by Ral guanine nucleotide dissociation stimulator (RalGDS) and phosphatidylinositol 3-kinase (PI3K). Apart from RAF, PI3K, RalGDS and p120 GAP the growing family of RAS effector proteins includes Rin1, Tiam, Af6, Nore1, PLCε and PKCζ. Currently there are more than 10 different RAS effectors (see Fig. 4 ), and several of them contain functionally related isoforms [97]. RAS effector proteins are characterized by the presence of a putative RAS binding domain or RBD. At least three distinct RBDs are recognized: (1) the RBD of RAF and TIAM 1, (2) the RBD from PI3K, and (3) the RAS association (RA) domains of RalGDS and AF6. The structures of the four RBDs solved so far displayed the same topology, the ubiquitin fold (ββαββαβ), suggesting a similar mode of interaction of RAS with its effectors [98].
Together, Raf, MEK, and the ERKs make up a three-tiered kinase signaling pathway called a mitogen-activated protein kinase ( MAPK) cascade. (A mitogen is a signal that causes cells to undergo mitosis, or divide.)
Generally, it takes on a new shape, which may make it active as an enzyme or let it bind other molecules. The change in the receptor sets off a series of signaling events.
The proteins present and the response produced are different in different types of cells. For instance, signaling in the β-cells of the pancreas leads to the release of insulin, while signaling in muscle cells leads to muscle contraction.
For signaling purposes, may be stored in compartments such as the endoplasmic reticulum.
Another second messenger used in many different cell types is cyclic adenosine monophosphate ( cyclic AMP or cAMP ), a small molecule made from ATP. In response to signals, an enzyme called adenylyl cyclase converts ATP into cAMP, removing two phosphates and linking the remaining phosphate to the sugar in a ring shape.
signal transduction. Many intracellular signaling proteins act as switches that toggle from an inactive to an active state. Once activated, these signaling proteins can stimulate—or in some cases inhibit—other proteins in the signaling pathway.
The GH-releasing hormone (GHRH) stimulates release of growth hormone (GH) from the pituitary gland by binding to GHRH receptors, which are G-protein-coupled receptors. Excessive activity of the GHRH signaling pathway leads to excessive release of growth hormone, which can lead to acromegaly, a form of gigantism.