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 controls a wide range of essential biochemical pathways in all eukaryotic cells. One of the most important functions of Ras proteins is activation of mitogen activated protein kinases (MAPK). MAPK pathways are important intracellular cascades that couple signals from the cell surface to the nucleus. One of the most explored functions of MAPK signaling modules is regulation of gene expression in response to extracellular stimuli. MAPK activity is regulated through three-tiered cascades composed of MAPK, MAPK kinase (MAPKK, MKK or MEK) and MAPKK kinase or MEK kinase (MAPKKK or MEKK) [1]. Members of Ras and Rho subfamilies could activate MAPK cascades by stimulating MEKK kinases.

Main effector of Ras subfamily members v-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-Ras), Neuroblastoma RAS viral (v-ras) oncogene homolog (N-Ras), and Related RAS viral (r-ras) oncogene homolog (R-Ras) is v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1) [2], [3], RAP1A, member of RAS oncogene family (RAP-1A) is a specific activator of v-raf murine sarcoma viral oncogene homolog B1 (B-Raf) [4], [5]. Activated Raf proteins phosphorylate Mitogen-activated protein kinase kinases 1 and 2 (MEK1(MAP2K1) and MEK2(MAP2K2)), which subsequently phosphorylate Mitogen-activated protein kinases 1 and 3 (ERK1/2) [1], [3]. ERK1/2 stimulation under Ras signaling leads to activation of a range of transcription factors, such as Jun oncogene (c-Jun), v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos), ELK1, member of ETS oncogene family (Elk-1), and CCAAT/enhancer binding protein (C/EBP), beta (C/EBP beta) [1], [6], [7], [8], [9].

Members of Rho subfamily ras-related C3 botulinum toxin substrate 1 (Rac1) and Cell division cycle 42 (CDC42) promotes activation of p21 protein (Cdc42/Rac)-activated kinase 1 (PAK1), Mitogen-activated protein kinase kinase kinases 1 and 4 (MEKK1(MAP3K1) and MEKK4(MAP3K4)), which phosphorylate Mitogen-activated protein kinase kinase 3 and 4 (MEK3(MAP2K3) and MEK4(MAP2K4)) and this leads to Mitogen-activated protein kinase 8 -10 (JNK(MAPK8-10)) and Mitogen-activated protein kinase 14 (p38 MAPK) activation [10], [11], [12], [13], [14]. Activated by Rac1 and CDC42 p38 MAPK and JNK(MAPK8-10) could activate their nuclear targets Activating transcription factor 2 (ATF-2) and c-Jun [15], [16].

In addition, H-RAS signaling can activate MEKK1(MAP3K1), which can promote ERK1/2 activation via c-Raf-1/MEK1(MAP2K1) or JNK(MAPK8-10) activation via MEK4(MAP2K4) [17], [18], [19], [20].

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