RGL2, CALDAG-GEFI, EGFR, Shc, EGF, Epo, RASSF1, c-Raf-1, KAP3, A-Raf-1, K-RAS, B-Raf, PKC-theta, SOS, RASGRF1, PI3K cat class IA (p110-alpha), Rap1GDS1, Epo receptor, Lck, RGL1, ICMT, CalDAG-GEFII, RalGDS, GRB2, FTase, CalDAG-GEFIII
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, 2 and 3 ( CALDAG-GEFII, CALDAG-GEFI, CALDAG-GEFIII ) , , 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 phosphorylation .
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 ( RASSF1 ) .