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) . 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) , , RAP1A, member of RAS oncogene family (RAP-1A) is
a specific activator of v-raf murine sarcoma viral oncogene homolog B1
(B-Raf) , . Activated Raf
proteins phosphorylate Mitogen-activated protein kinase kinases 1 and 2
MEK2(MAP2K2)), which subsequently phosphorylate
Mitogen-activated protein kinases 1 and 3 (ERK1/2) , . 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) , , , , .
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 , , , , . 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 , .
In addition, H-RAS signaling can activate
MEKK1(MAP3K1), which can promote
ERK1/2 activation via
JNK(MAPK8-10) activation via
MEK4(MAP2K4) , , , .
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Expression of human cystatin A by keratinocytes is positively regulated via the Ras/MEKK1/MKK7/JNK signal transduction pathway but negatively regulated via the Ras/Raf-1/MEK1/ERK pathway.
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