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G-protein signaling K-RAS regulation pathway


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G-protein signaling K-RAS regulation pathway

K-RAS regulation pathway

V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( K-RAS ) belongs to Rasfamily of small GTPases and serves as a signal transducer from growth factor receptorsand activates numerous effector molecules resulting in cell growth, differentiation andapoptosis [1], [2].

Guanine nucleotide exchange factors (GEFs) are essential for K-RAS activation[2]. Main GEFs for K-RAS are RAS guanyl releasing proteins 1, 2 and 3( CALDAG-GEFII, CALDAG-GEFI, CALDAG-GEFIII ) [3],[4], Ras protein-specific guanine nucleotide-releasing factor 1 (RASGRF1 ), which is activated by Lymphocyte-specific protein tyrosine kinase (Lck ) phosphorylation [5], and RAP1 GTP-GDP dissociation stimulator 1( Rap1GDS1 ), which is stimulated by Kinesin-associated protein 3 ( KAP3 )binding [6].

K-RAS activation can be induced by Erythropoietin ( Epo ) and Epidermalgrowth factor ( EGF ) signaling [7], [8]. ActivatedErythropoietin receptor ( Epo receptor ) and Epidermal growth factor receptor (EGFR ) associate with SHC (Src homology 2 domain containing) transforming protein1 ( Shc ), which binds to Growth factor receptor-bound protein 2 ( GRB2 )and this leads to Son of sevenless homolog ( SOS ) activation [9],[10], [11]. SOS promotes GTP loading on K-RAS andits activation [4].

K-RAS undergoes several posttranslational modifications that are essential forits proper plasma membrane localization. K-RAS modifications are also necessaryfor the biological function of the modified protein. Isoprenylcysteine carboxylmethyltransferase ( ICMT ) promotes carboxyl methylation of K-Ras andfarnesyltransferase, CAAX box ( FTase ) catalyzes K-RAS farnesylation[12], [13], [14].

Subcellular localization and function of K-Ras are also modulated by Proteinkinase C theta ( PKC-theta )-mediated phosphorylation [15].

The best characterized K-Ras effectors are: the Raf kinase family thatcomprises v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 ), v-rafmurine sarcoma 3611 viral oncogene homolog ( A-Raf-1 ), and v-raf murine sarcomaviral oncogene homolog B1 ( B-Raf ), through which K-Ras activates themitogen-activated protein kinase (MAPK) cascade [1], [2]; thePhosphoinositide-3-kinase, catalytic, alpha polypeptide ( PI3K cat class IA(p110-alpha) ) [16], and the family of RalGEFs that now includes Ralguanine nucleotide dissociation stimulator ( RalGDS ), Ral guanine nucleotidedissociation stimulator-like 1 and 2 ( RGL1 and RGL2 ) [17].Also, activated farnesylated K-RAS can form a complex with Ras association (RalGDS/AF-6)domain family member 1 ( RASSF1 ) [18].