Disease relevance of Rala

• Signal pathways which promote invasion and metastasis: critical and distinct contributions of extracellular signal-regulated kinase and Ral-specific guanine exchange factor pathways [1].
• Clostridium sordellii lethal toxin (TcsL) is a large clostridial toxin (LCT) that glucosylates Ras, Rac, and Ral [2].
• This work identifies a new potential function for p130(Cas) and a new regulatory pathway involved in the control of Ral, Rap, and R-Ras GTPases that may participate in the progression of breast cancer cells to tamoxifen resistance [3].
• JAK/STAT3-dependent activation of the RalGDS/Ral pathway in M1 mouse myeloid leukemia cells [4].

High impact information on Rala

• Thus RalA is involved in the tyrosine kinase activation of PLD through its unique N terminus, and that PLD is a downstream target of a Ras/Ral GTPase cascade [5].
• This Ral-mediated, JNK-dependent phosphorylation is involved in the nuclear translocation and transcriptional activation of FOXO4 after H2O2 treatment [6].
• The results reported here, therefore, outline a homeostasis mechanism for sustaining cellular reactive oxygen species that is controlled by signalling pathways that can convey both negative (PI-3K/PKB) and positive (Ras/Ral) inputs [6].
• Rlf, when targeted to the plasma membrane using the Ras farnesyl attachment site (Rlf-CAAX), is constitutively active, inducing both Ral activation and c-fos promoter activity [7].
• From three known effectors which retain the ability to interact with Ras(V12G37), overexpression of phospholipase C epsilon but not that of RIN1 or Ral guanine nucleotide exchange factors enhanced cytokine and nuclear factor-activated T cell reporter T cell responses [8].

Chemical compound and disease context of Rala

• We developed a raloxifene-resistant MCF-7 cell model (MCF-7/Ral) and investigated the nature of raloxifene-resistant breast cancer and its response to estradiol [9].

Biological context of Rala

• To further delineate R-Ras downstream signaling events, we observed that while a dominant negative mutant of Akt/protein kinase inhibited the ability of R-Ras to promote cell survival, both dominant negative mutants of Rac and Ral suppressed cell adhesion stimulated by R-Ras [10].
• To investigate if Ral GTPases play a role in development, temporal and spatial patterns of RalA and RalB gene expression were examined during embryogenesis [11].
• From these results we conclude that Ral-mediated phosphorylation of threonines 447 and 451 is required for proper activity of AFX-WT [12].
• Furthermore, inhibition of Ral-GEF activity by expression of a dominant negative Ral mutant accelerated cell cycle arrest and enhanced neurite outgrowth in response to NGF treatment [13].
• RalBP1 is a potential effector protein of small GTP-binding protein Ral and regulates endocytosis of epidermal growth factor and insulin receptors [14].

Anatomical context of Rala

• We show that inhibition of Ral signaling blocks DNA synthesis in human tumor cell lines containing activating mutations in TC21, demonstrating for the first time that this pathway is required for the proliferation of human tumor cells [15].
• In contrast, the addition of recombinant Ral proteins (RalA and RalB), glucosylation substrates for TscL and TcdB-1470, but not for TcdB, to membranes of TcdB-1470- or TcsL-treated cells fully restored PLD stimulation by PMA without altering the strict MgATP dependence of PMA-induced PLD stimulation [16].
• In addition, retrovirus-mediated expression of dominant-negative versions of Ras and Ral led to a reduced migration of transplanted myoblasts in vivo [17].
• Ral-GTPase influences the regulation of the readily releasable pool of synaptic vesicles [18].
• Involvement of Ras and Ral in chemotactic migration of skeletal myoblasts [19].

Associations of Rala with chemical compounds

• Finally, Ral-GDS belongs to a family of guanine nucleotide exchange factors that activate Ral GTPases [20].
• When cultured with 1 microM raloxifene, MCF-7/Ral cells grew statistically significantly (P<.001) faster than MCF-7 cells [9].
• Treatment with either raloxifene or tamoxifen stimulated MCF-7/Ral tumor growth, suggesting that such tumors were resistant to both drugs [9].

Physical interactions of Rala

• Moreover, we have identified that the COOH-terminal region of ARIP2 interacts with Ral-binding protein 1 (RalBP1) [14].

Regulatory relationships of Rala

• Rap1-activated Ral and Ral-DN blocked Rap-induced Src phosphorylation [21].

Other interactions of Rala

• This establishes a novel role for the Ral-GEF pathway in regulating p27 localization [22].
• In this study, we examined the effects of RalGDS and Ral on gene expression using c-fos promoter linked to the luciferase reporter gene (c-fos-luciferase) [23].

Analytical, diagnostic and therapeutic context of Rala

• This mapping, along with available site-directed mutagenesis data, allows us to predict how Ral and Sec5 may interact [24].

References