Cross-talk between Ras-family GTPases
GTPases of the Ras superfamily act as molecular switches to control a wide range of
essential biochemical pathways in all eukaryotic cells. The members of this superfamily
are structurally classified into at least five families: Ras, Rho, Rab, Sar1/Arf, and Ran
. Different members of Ras-family form signaling cascades that are
involved in various cellular functions acting in a cooperative or antagonistic manner.
Thus, Ras GTPases appear to exert their functions through their mutual crosstalk and
multiple downstream effectors in a variety of cellular functions , .
Ras GTPases have two interconvertible forms: GDP-bound inactive and GTP-bound active
forms. Guanine nucleotide exchange factors (GEFs) promote GTP loading essential for Ras
GTPase activation. GTPase activating proteins (GAPs) stimulate hydrolysis of GTP to GDP
which negatively regulates Ras protein activity .
GEFs and GAPs also can be downstream effectors of Ras proteins. RAS p21 protein
activator 1 (p120GAP) modulates activity of v-Ha-ras Harvey
rat sarcoma viral oncogene homolog (H-Ras) ,
and thus influences activation of H-Ras-induced Phosphoinositide-3-kinase, catalytic
(PI3K cat class IA)/ V-Akt murine thymoma viral oncogene
homolog (AKT(PKB)) signaling and stimulation of Ral guanine
nucleotide dissociation stimulator (RalGDS) and T-cell
lymphoma invasion and metastasis 1 (Tiam1).
RalGDS and Tiam1, in turn, are
GEFs for V-ral simian leukemia viral oncogene homolog A
(RalA) and Ras-related C3 botulinum toxin substrate 1
(Rac1) , , , .
Another member of Ras family Muscle RAS oncogene homolog
(M-RAS) regulated by p120GAP
can modulate activity of Rap guanine nucleotide exchange factor 5
(MR-GEF). MR-GEF is a GEF for
RAP1A member of RAS oncogene family (RAP-1A) . In turn, RAP-1A binds to and inhibits
p120GAP negatively regulates activity of Rho GTPase
activating protein 5 (RhoGAP5). RhoGAP5
is a common GAP for Rho subfamily members
Rac1, Cell division cycle 42
(CDC42) and Ras homolog gene family, member A
(RhoA) . V-ral simian leukemia viral oncogene
homolog A (RalA) also can influence
Rac1 and CDC42 activity by
regulation of their common GAP, RalA binding protein 1
(RalBP1) . Activated
Rac1 in turn can activate MCF.2 cell line derived
transforming sequence-like (DBS), common activator for
CDC42 and RhoA .
Ras family members can intersect its cellular function at the level of common
downstream targets and cascades. Rac1,
RhoA and RalA promote
Phospholipase D1, phosphatidylcholine-specific (PLD1)
activation . H-Ras and
RAP-1A common effectors are: the Raf kinase family members
v-raf-1 murine leukemia viral oncogene homolog 1 (c-Raf-1)
and v-raf murine sarcoma viral oncogene homolog B1 (B-Raf).
Thus H-Ras and RAP-1A promote
MAPK cascade activation that is also common for Rac1 and
CDC42 , , .
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