Pathway Map Details
Cytoskeleton remodeling_RalA regulation pathway
Object list (links open in MetaCore):
18.104.22.168, RAP-1A, Rac1, Aurora-A, Beta-arrestin2, RalA, RGL, RalGEF2, Ca('2+) cytosol, Beta-arrestin1, PLD1, 1,2-diacyl-glycerol 3-phosphate, Sec15B, Actin, REPS1, Calmodulin, AP complex 2 medium (mu) chain, FPR, RalGDS, RalBP1, CDC42, Sec5, H-Ras, GGTase-I, REPS2, Phosphatidylcholine, Filamin A, HSF1, Sec6, ARF1
RalA regulation pathway
v-Ral simian leukemia viral oncogene homolog A ( RalA ) belongs to a family of small GTP-binding proteins (G-proteins) called monomeric G-proteins. The Ral subfamily consists of RalA and RalB proteins.
RalA is localized at the cytoplasmic surface of the plasma membrane. It is a target of posttranslational modification via attachment of lipid moieties, such as geranyl, catalyzed by Geranylgeranyltransferase type I ( GGTase-I ). These posttranslational modifications affect localization and biological activity of RalA .
Like other G-proteins , RalA is found in two interconvertible forms, GDP-bound inactive and GTP-bound active. Conversion from the GDP- to GTP-bound form is catalyzed by Guanine nucleotide exchange factors (GEFs). Activity of GEF is often regulated by an upstream signal. GEF first interacts with the GDP-bound form and releases bound GDP. As a result, a binary complex of a small G protein and GEF is formed. GEF in this complex is subsequently replaced by GTP resulting in formation of the GTP-bound small G protein .
Three GEFs are known to interact with RalA. These are RalGDS, RGL, and RalGEF2. Two of them, RalGDS and RGL, have been found to be v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-RAS ) protein effectors , . They also bind RAP1A member of RAS oncogene family ( RAP-1A ), but biological role of these interactions is unclear , .
RalGDS activity is affected by Formyl-Met-Leu-Phe receptor ( FPR ). RalGDS is localized to the cytosol and remains inactive in a complex formed with Beta-arrestins ( Beta-arrestin 1 and Beta-arrestin 2 ). In response to FPR stimulation, Beta-arrestin/ RallGDS protein complexes dissociate, and RalGDS translocates with Beta-arrestin from the cytosol to the plasma membrane. This leads to activation of the RalA effector pathway that affects cytoskeletal rearrangements .
Conversion from GTP-bound form to GDP-bound form is a result of intrinsic GTPase activity of RalA. This activity is slow, and proteins called GTPase activated proteins (GAPs) are known to stimulate it. The GAP proteins for RalA were characterized and partially purified. However, their genes have not been cloned yet .
Aurora kinase ( Aurora -A) phosphorylates and activites RalA . Ral GTPases may also be involved in calcium/calmodulin-mediated intracellular signaling pathways where RalA is activated by Ca(2+) via binding with Calmodulin .
Effectors for RalA RalBP1, Phospholipase D 1 ( PLD1), Filamin, and components of the exocyst implicate participation RalA in various cell processes .
RalBP1 contains a RhoGAP homology domain that exhibits the GAP activity for Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) and Cell division cycle 42 ( CDC42 ) proteins, thereby inhibiting Rac1/ CDC42 involved in cytoskeleton remodeling . On the other hand, actin-binding protein Filamin is an effector protein of RalA. Filamin crosslinks Actin filaments into orthogonal networks and participates in the anchoring of membrane proteins to the Actin cytoskeleton .
RalA via RalBP1 interacts with the Mu-subunit of the heterotetrameric Coat assembly protein complex 2 ( AP complex 2 medium (mu) chain ) and RALBP1 associated Eps domain containing 1 and 2 ( REPS1 and REPS2 ) proteins. These proteins are involved in endocytosis and cell motility , , .
RalBP1 also interacts with the stress-responsive Heat shock factor 1 ( HSF1 ) and regulates its activity .
Another RalA protein effector, PLD1, is implicated in vesicle trafficking. PLD1 directly associates with RalA. However, RalA has no effect on the activity of the PLD1. RalA is required for the stimulation of PLD1 activity by the ADP-ribosylation factor 1 ( ARF1 ) .
Thus the RalA signaling appears to regulate vesicle trafficking, cytoskeleton organization, gene expression, and cell transformation.
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