p120GAP, RalGDS, PDK (PDPK1), RalA, DBS, c-Raf-1, MR-GEF, H-Ras, Rac1, M-RAS, PtdIns(4,5)P2, RhoA, Tiam1, RAP-1A, RhoGAP5, RalBP1, 18.104.22.168, PtdIns(3,4,5)P3, CDC42, PI3K cat class IA, PLD1, AKT(PKB), B-Raf
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 . 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 , , .