K-RAS regulation pathway
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
(K-RAS) belongs to Ras family of small GTPases and serves as
a signal transducer from growth factor receptors and activates numerous effector
molecules resulting in cell growth, differentiation and apoptosis , .
Guanine nucleotide exchange factors (GEFs) are essential for
K-RAS activation . Main GEFs for
K-RAS are RAS guanyl releasing proteins 1 and 2
, , Ras protein-specific guanine nucleotide-releasing
factor 1 (RASGRF1), which is activated by
Lymphocyte-specific protein tyrosine kinase (Lck)
phosphorylation , and RAP1 GTP-GDP dissociation stimulator 1
(Rap1GDS1), which is stimulated by Kinesin-associated
protein 3 (KAP3) binding .
K-RAS activation can be induced by Erythropoietin
(Epo) and Epidermal growth factor
(EGF) signaling , .
Activated Erythropoietin receptor (Epo receptor) and
Epidermal growth factor receptor (EGFR) associate with SHC
(Src homology 2 domain containing) transforming protein 1
(Shc), which binds to Growth factor receptor-bound protein 2
(GRB2) and this leads to Son of sevenless homolog
(SOS) activation , , . SOS promotes GTP loading on
K-RAS and its activation .
K-RAS undergoes several posttranslational modifications
that are essential for its proper plasma membrane localization.
K-RAS modifications are also necessary for the biological
function of the modified protein. Isoprenylcysteine carboxyl methyltransferase
(ICMT) promotes carboxyl methylation of
K-Ras and farnesyltransferase, CAAX box
(FTase) catalyzes K-RAS
farnesylation , , .
Subcellular localization and function of K-Ras are also
modulated by Protein kinase C theta (PKC-theta)-mediated
The best characterized K-Ras effectors are: the Raf
kinase family that comprises 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 K-Ras
activates the mitogen-activated protein kinase (MAPK) cascade , ; the Phosphoinositide-3-kinase, catalytic, alpha polypeptide
(PI3K cat class IA (p110-alpha)) , and the
family of RalGEFs that now includes Ral guanine nucleotide dissociation stimulator
(RalGDS), Ral guanine nucleotide dissociation
stimulator-like 1 and 2 (RGL1 and
RGL2) . Also, activated farnesylated K-RAS
can form a complex with Ras association (RalGDS/AF-6) domain family member 1
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