N-RAS regulation pathway
Neuroblastoma RAS viral (v-ras) oncogene homolog (N-RAS)
belongs to Ras family of small GTPases. It serves as a signal transducer from growth
factor receptors and activates numerous effector molecules resulting in cell growth,
differentiation and survival , . Guanine nucleotide
exchange factors (GEFs) are essential for N-RAS activation
N-RAS activation can be induced by Epidermal growth
factor (EGF) signaling . Activated Epidermal
growth factor receptor (EGFR) associates with SHC (Src
homology 2 domain containing) transforming protein 1 (Shc)
and Growth factor receptor-bound protein 2 (GRB2) and this
leads to Son of sevenless homolog (SOS) activation , . Activated SOS promotes GTP
loading on N-RAS and its activation .
Ras activation is critical for T-cell development and function. Upon engagement of the
T cell receptor (TCR alpha/beta - CD3
complex) by antigen presented on Major histocompatibility complex, class
II (MHC class II) molecules, CD4 molecule
(CD4)-bound Lymphocyte-specific protein tyrosine kinase
(Lck) is activated and proceeds to phosphorylate CD247
molecule (CD3 zeta). This promotes the recruitment and
subsequent activation of Zeta-chain (TCR) associated protein kinase 70kDa
(ZAP70). ZAP70 binds to Linker
for activation of T cells (LAT) which recruits Phospholipase
C gamma 1 (PLC-gamma 1). Activated PLC-gamma
1 is responsible for the production of the second messenger
1,2-diacyl-glycerol (DAG). This activates RAS guanyl
releasing protein 1
(CALDAG-GEFII), a known
GEF for N-RAS , , .
Other known GEF for N-RAS is RAS guanyl releasing protein
2 (CALDAG-GEFI) , . These
proteins can be activated by increased Ca(2'+) cytosol and
DAG levels ,  as well as by
Ras protein-specific guanine nucleotide-releasing factor 1
(RASGRF1) thet can be activated by
Lck phosphorylation .
N-RAS undergoes posttranslational modifications by
Isoprenylcysteine carboxyl methyltransferase (ICMT) which
promotes carboxyl methylation of N-Ras essential for its
proper localization and cell function , , .
The best characterized N-Ras effectors are: the Raf
kinase family comprised of v-raf-1 murine leukemia viral oncogene homolog 1
(c-Raf-1), v-raf murine sarcoma 3611 viral oncogene homolog
(A-Raf-1), and v-raf murine sarcoma viral oncogene homolog
B1 (B-Raf), through which N-Ras
activates the mitogen-activated protein kinase (MAPK) cascade , , , and a family of RalGEFs that now includes Ral guanine
nucleotide dissociation stimulator (RalGDS), Ral guanine
nucleotide dissociation stimulator-like 1 and 2 (RGL1 and
RGL2) , .
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Ras and relatives--job sharing and networking keep an old family together.
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T cell receptor signalling.
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Integration of calcium and Ras signalling.
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