Ras-GRF1 explained

Ras protein-specific guanine nucleotide-releasing factor 1
Hgncid:9875
Symbol:RASGRF1
Altsymbols:GRF1
Entrezgene:5923
Omim:606600
Refseq:NM_153815
Uniprot:Q13972
Chromosome:15
Arm:q
Band:24

Ras-GRF1 is a guanine nucleotide exchange factor. Its function is to release guanosine diphosphate, GDP, from the signaling protein RAS, thus increasing the activity of RAS by allowing it to bind to guanosine triphosphate, GTP, returning it to its active state. In this way, Ras-GRF1 has a key role in regulating the RAS signaling pathway. Ras-GRF1 mediates the activation of RAS via Ca2+ bound calmodulin protein.[1]

Function

Activation of Ras proteins occur through the phosphorylation of tyrosine receptors. This recruits adapter protein GRB2 which binds to SOS exchange factors, that bind and activate Ras. Ras/MAPK pathways is activated by the intracellular calcium that binds to the ilimaquinone domain (IQ) on Ras-GRF1.[2] Activated Ras can go on to activate Raf/Mek/Erk kinases which can mediate the activation of CREB transcription factors. This can affect gene expression and cell proliferation. [3]

Ras-GRF1 knockout mice have been shown to have learning and memory deficits associated with dysregulation of this pathway.[4] Ras-GRF1 has also been shown to be upstream from IGF1, allowing it to control growth in mice.[5] Although it is sometimes known as CDC25, it should not be confused with Cdc25. Ras-GRF1 is a paternally expressed imprinted gene, meaning that only the paternal allele of the gene is translated into protein. Disruption of this epigenetic imprinting also produces learning and memory deficits in neonatal mice.[6]

Ras-GRF1 has been shown to mediate long term potentiation (LTP), affecting memory and learning. A signaling pathway involving Ras-GRF1/p38 MAP/CP -AMPAR has been shown to affect LTP. Ras-GRF1 knockout mice, induced with high frequency stimulation to induce LTP (HFS-LTP), displayed the inability to retain memory and distinguish similar concepts. A Ras-GRF1/ERK pathway has also been found to affect the activity of LTP in medium spiny neuron (MSN) pathways. Ras-GRF1 knockout mice treated with HFS-LTP have exhibited the inability to induce LTP in direct MSN pathways. Ras-GRF1 signaling has been thought to be involved with L-DOPA-induced dyskinesia, a condition in which LTP and MSN homeostasis are disrupted.[7]

Alongside its regulation of learning and memory, Ras-GRF1 has exhibited the ability to impact pancreatic β-cell proliferation. Ras-GRF1 knockout mice have expressed decreased pancreatic β-cell concentration and activity. Reduction of β-cell mass and area has correlated to a decrease in circulating insulin levels, exposing a Ras-GRF1 signaling pathway that regulates glucose metabolism.[8]

References

  1. Jin . Shan-Xue . Arai . Junko . Tian . Xuejun . Kumar-Singh . Rajendra . Feig . Larry A. . 2013-07-26 . Acquisition of Contextual Discrimination Involves the Appearance of a RAS-GRF1/p38 Mitogen-activated Protein (MAP) Kinase-mediated Signaling Pathway That Promotes Long Term Potentiation (LTP) . Journal of Biological Chemistry . 288 . 30 . 21703–21713 . 10.1074/jbc.m113.471904 . 23766509 . 0021-9258. free . 3724629 .
  2. Brambilla . Riccardo . Gnesutta . Nerina . Minichiello . Liliana . White . Gail . Roylance . Alistair J. . Herron . Caroline E. . Ramsey . Mark . Wolfer . David P. . Cestari . Vincenzo . Rossi-Arnaud . Clelia . Grant . Seth G. N. . Chapman . Paul F. . Lipp . Hans-Peter . Sturani . Emmapaola . Klein . Rdiger . November 1997 . A role for the Ras signalling pathway in synaptic transmission and long-term memory . Nature . en . 390 . 6657 . 281–286 . 10.1038/36849 . 1997Natur.390..281B . 0028-0836.
  3. Tian . Xuejun . Gotoh . Takaya . Tsuji . Kiyoshi . Lo . Eng H . Huang . Su . Feig . Larry A . 2004-04-07 . Developmentally regulated role for Ras-GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB . The EMBO Journal . 23 . 7 . 1567–1575 . 10.1038/sj.emboj.7600151 . 0261-4189 . 391062 . 15029245.
  4. Fernandez-Medarde A, Porteros A, De Las Rivas J, Nunez A, Fuster JJ, Santos E . 2007 . Laser microdissection and microarray analysis of the hippocampus of Ras-GRF1 knockout mice reveals gene expression changes affecting signal transduction pathways related to memory and learning . Neuroscience . 146 . 1 . 272–285 . 10.1016/j.neuroscience.2007.01.022 . 17321057. 20255066 .
  5. Drake NM, Park YJ, Shirali AS, Cleland TA, Soloway PD . 2009 . Imprint switch mutations at Rasgrf1 support conflict hypothesis of imprinting and define a growth control mechanism upstream of IGF1 . Mamm. Genome . 20 . 9–10 . 654–63 . 10.1007/s00335-009-9192-7 . 2919583 . 19513790.
  6. Drake NM, DeVito LM, Cleland TA, Soloway PD . 2011 . Imprinted Rasgrf1 expression in neonatal mice affects olfactory learning and memory . Genes Brain Behav . 10 . 4 . 392–403 . 10.1111/j.1601-183X.2011.00678.x . 3091993 . 21251221.
  7. Cerovic . Milica . Bagetta . Vincenza . Pendolino . Valentina . Ghiglieri . Veronica . Fasano . Stefania . Morella . Ilaria . Hardingham . Neil . Heuer . Andreas . Papale . Alessandro . Marchisella . Francesca . Giampà . Carmela . 2015-01-15 . Derangement of Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Extracellular Signal-Regulated Kinase (ERK) Dependent Striatal Plasticity in L-DOPA-Induced Dyskinesia . Biological Psychiatry . 77 . 2 . 106–115 . 10.1016/j.biopsych.2014.04.002 . 24844602 . 16764086 . 0006-3223. 2434/731011 . free .
  8. Font de Mora . J. . 2003-06-16 . Ras-GRF1 signaling is required for normal-cell development and glucose homeostasis . The EMBO Journal . 22 . 12 . 3039–3049 . 10.1093/emboj/cdg280 . 12805218 . 162132 . 1460-2075.

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