RalGDS family members couple Ras to Ral signalling and that's not all

Ferro, Elisa; Trabalzini, Lorenza

doi:10.1016/j.cellsig.2010.05.010

Cited by 71 publications

(60 citation statements)

References 79 publications

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“…Positive feedback on Notch expression has also been observed in T-cell precursors (Yashiro-Ohtani et al, 2009), as well as in C. elegans (Christensen et al, 1996), and is likely to be important in maintaining Notch receptor levels in signalling cells as the process of activation results in destruction of the receptor (Kopan and Ilagan, 2009). Another common target in Kc and DmD8 cells encodes Rgl, a member of the RalGEF family that is suggested to couple Ras to Ral signalling (Ferro and Trabalzini, 2010). The shared and related targets from the Kc and DmD8 cells may thus identify core elements in the Notch response that are relevant in many different contexts.…”

Section: Discussionmentioning

confidence: 99%

Notch cooperates with Lozenge/Runx to lock haemocytes into a differentiation programme

et al. 2013

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SUMMARYThe diverse functions of Notch signalling imply that it must elicit context-specific programmes of gene expression. With the aim of investigating how Notch drives cells to differentiate, we have used a genome-wide approach to identify direct Notch targets in Drosophila haemocytes (blood cells), where Notch promotes crystal cell differentiation. Many of the identified Notch-regulated enhancers contain Runx and GATA motifs, and we demonstrate that binding of the Runx protein Lozenge (Lz) is required for enhancers to be competent to respond to Notch. Functional studies of targets, such as klumpfuss (ERG/WT1 family) and pebbled/hindsight (RREB1 homologue), show that Notch acts both to prevent the cells adopting alternate cell fates and to promote morphological characteristics associated with crystal cell differentiation. Inappropriate activity of Klumpfuss perturbs the differentiation programme, resulting in melanotic tumours. Thus, by acting as a master regulator, Lz directs Notch to activate selectively a combination of target genes that correctly locks cells into the differentiation programme.

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Section: Discussionmentioning

confidence: 99%

Notch cooperates with Lozenge/Runx to lock haemocytes into a differentiation programme

et al. 2013

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“…The RalGDS can directly interact with GTP-bound active form of Ras protein through their Ras binding domain (RBD) (37), and interaction between GTP-Ras and RalGDS promote the translocation of RalGDS to the plasma membrane where it activates Ral (38). The RalGDSRal pathway has been shown to be involved in regulation of various transcription factors, such as Rlf, c-Jun, and ATF2, to promote cell proliferation (39)(40)(41).…”

Section: A B C D E Fmentioning

confidence: 99%

MEK1/2 Inhibitors AS703026 and AZD6244 May Be Potential Therapies for KRAS Mutated Colorectal Cancer That Is Resistant to EGFR Monoclonal Antibody Therapy

2011

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Epidermal growth factor receptor (EGFR) monoclonal antibodies (mAb) are used widely to treat metastatic colorectal cancer (mCRC) patients, but it is now clear that patients harboring K-ras mutation are resistant to EGFR mAbs such as cetuximab (Erbitux) and panitumumab (Vectibix). For this reason, current recommendations for patient care involve diagnosing the K-ras mutational status of patients prior to EGFR mAb therapy. In this study, we investigated the ability of two MEK inhibitors currently in clinical trials, AS703026 and AZD6244, to address the challenge posed by the resistance of K-ras mutated colorectal cancers to EGFR mAb. AS703026 and AZD6244 were tested in various cell-based assays and tumor xenograft studies, focusing on isogenic human colorectal tumor cell lines that expressed only WT or mutant K-Ras (D-WT or D-MUT). The EGFR mAb cetuximab inhibited the Ras-ERK pathway and proliferation of D-WT cells in vitro and in vivo, but it did not inhibit proliferation of D-MUT cells in either setting. In contrast, AS703026 and AZD6244 effectively inhibited the growth of D-MUT cells in vitro and in vivo by specific inhibition of the key MEK downstream target kinase ERK. Inhibition of MEK by AS703026 or AZD6244 also suppressed cetuximab-resistant colorectal cancer cells attributed to K-ras mutation both in vitro and in vivo. Our findings offer proof-of-concept for the use of MEK inhibitors as an effective therapy in K-ras mutated CRC. Cancer Res; 71(2); 445-53. Ó2010 AACR.

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“…As discussed above, Ras/Map kinase plays a key role in promoting cell cycle re-entry and progression. PI3K-AKT is involved in cell survival, while RalGDS is one of several Ras-regulated guanine-nucleotide exchange factors that activates Ral A and B GTPases (Carnero, et al, 2008, Ferro & Trabalzini, 2010. Ral proteins regulate key cellular processes such as endocytosis, exocytosis, and actin organization, as well as contributing to regulation of gene expression (Carnero, et al, 2008, Ferro & Trabalzini, 2010.…”

Section: Mutational Activation Of Ras Signalingmentioning

confidence: 99%