G-protein signaling Ras family GTPases in kinase cascades (scheme)
Ras family GTPases in kinase cascades GTPases of the Ras superfamily are activated upon growth factors stimuli and controlsa wide range of essential biochemical pathways in all eukaryotic cells. One of the mostimportant functions of Ras proteins is activation of mitogen activated protein kinases(MAPK). MAPK pathways are important intracellular cascades that couple signals from thecell surface to the nucleus. One of the most explored functions of MAPK signaling modulesis regulation of gene expression in response to extracellular stimuli. MAPK activity isregulated through three-tiered cascades composed of MAPK, MAPK kinase (MAPKK, MKK or MEK)and MAPKK kinase or MEK kinase (MAPKKK or MEKK) . Members of Ras and Rhosubfamilies could activate MAPK cascades by stimulating MEKK kinases. Main effector of Ras subfamily members v-Ha-ras Harvey rat sarcoma viral oncogenehomolog ( H-Ras), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras), Neuroblastoma RAS viral (v-ras) oncogene homolog ( N-Ras), andRelated RAS viral (r-ras) oncogene homolog ( R-Ras) is v-raf-1 murine leukemiaviral oncogene homolog 1 ( c-Raf-1) , , RAP1A,member of RAS oncogene family ( RAP-1A) is a specific activator of v-raf murinesarcoma viral oncogene homolog B1 ( B-Raf) , .Activated Raf proteins phosphorylate Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) and MEK2(MAP2K2) ), which subsequently phosphorylateMitogen-activated protein kinases 1 and 3 ( ERK1/2) , . ERK1/2 stimulation under Ras signaling leads to activation of a rangeof transcription factors, such as Jun oncogene ( c-Jun), v-fos FBJ murineosteosarcoma viral oncogene homolog ( c-Fos), ELK1, member of ETS oncogene family( Elk-1), and CCAAT/enhancer binding protein (C/EBP), beta ( C/EBP beta), , , , . Members of Rho subfamily ras-related C3 botulinum toxin substrate 1 ( Rac1) andCell division cycle 42 ( CDC42) promotes activation of p21 protein(Cdc42/Rac)-activated kinase 1 ( PAK1), Mitogen-activated protein kinase kinasekinases 1 and 4 ( MEKK1(MAP3K1) and MEKK4(MAP3K4) ), which phosphorylateMitogen-activated protein kinase kinase 3 and 4 ( MEK3(MAP2K3) andMEK4(MAP2K4) ) and this leads to Mitogen-activated protein kinase 8 -10 (JNK(MAPK8-10) ) and Mitogen-activated protein kinase 14 ( p38 MAPK)activation , , , , . Activated by Rac1 and CDC42 p38 MAPK andJNK(MAPK8-10) could activate their nuclear targets Activating transcription factor2 ( ATF-2) and c-Jun , . In addition, H-RAS signaling can activate MEKK1(MAP3K1), which canpromote ERK1/2 activation via c-Raf-1/ MEK1(MAP2K1) orJNK(MAPK8-10) activation via MEK4(MAP2K4) , ,, .