RasGRP4, a New Mast Cell-restricted Ras Guanine Nucleotide-releasing Protein with Calcium- and Diacylglycerol-binding Motifs

Yang, Yi; Li, Lixin; Wong, G. William; Krilis, Steven A.; Madhusudhan, M.S.; Šali, Andrej; Stevens, Richard L

doi:10.1074/jbc.m202575200

Cited by 92 publications

(79 citation statements)

References 66 publications

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“…Aberrant processing of mRNAs in tumor cells has been described for the MDM2, RasGRP4, SLP-65, TLE1, TLE4, MTA1 and CD44 genes and is emerging as an important characteristic of tumor cells (Bartel et al, 2002;Kumar et al, 2002;Reuther et al, 2002;Yang et al, 2002;Jumaa et al, 2003;Venables, 2004;Watermann et al, 2006) and is observed in other diseases, such as myotonic dystrophy (Charlet-B et al, 2002). In aberrant splicing, portions of exons, portions of introns or both are retained within transcripts that fail to be purged by the cellular pathways designed to scavenge abnormal mRNAs, such as nonsense-mediated decay (Culbertson, 1999;Wilkinson and Shyu, 2002).…”

Section: Discussionmentioning

confidence: 99%

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

et al. 2007

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Cancer cells display an altered distribution of DNA methylation relative to normal cells. Certain tumor suppressor gene promoters are hypermethylated and transcriptionally inactivated, whereas repetitive DNA is hypomethylated and transcriptionally active. Little is understood about how the abnormal DNA methylation patterns of cancer cells are established and maintained. Here, we identify over 20 DNMT3B transcripts from many cancer cell lines and primary acute leukemia cells that contain aberrant splicing at the 5 0 end of the gene, encoding truncated proteins lacking the C-terminal catalytic domain. Many of these aberrant transcripts retain intron sequences. Although the aberrant transcripts represent a minority of the DNMT3B transcripts present, Western blot analysis demonstrates truncated DNMT3B isoforms in the nuclear protein extracts of cancer cells. To test if expression of a truncated DNMT3B protein could alter the DNA methylation patterns within cells, we expressed DNMT3B7, the most frequently expressed aberrant transcript, in 293 cells. DNMT3B7-expressing 293 cells have altered gene expression as identified by microarray analysis. Some of these changes in gene expression correlate with altered DNA methylation of corresponding CpG islands. These results suggest that truncated DNMT3B proteins could play a role in the abnormal distribution of DNA methylation found in cancer cells.

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Section: Discussionmentioning

confidence: 99%

Cancer cells express aberrant DNMT3B transcripts encoding truncated proteins

et al. 2007

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“…5). Each RasGRP activates either Ras or Rap1, except RasGRP3, which is unique because it facilitates exchange for both Ras and Rap1 (6)(7)(8)(9)(10).…”

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confidence: 99%

Diacylglycerol kinase ι regulates Ras guanyl-releasing protein 3 and inhibits Rap1 signaling

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et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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To study the physiological function of diacylglycerol (DAG) kinase (DGK ), which converts DAG to phosphatidic acid, we deleted this gene in mice. In contrast to previous studies showing that DGK isoforms decrease Ras activity, signaling downstream of Ras in embryonic fibroblasts was significantly reduced in cells lacking DGK . DGKs regulate Ras signaling by attenuating the function of the DAG-dependent Ras guanyl nucleotide-releasing proteins (RasGRPs). We tested whether DGK inhibited the four known RasGRPs and found that it inhibited only RasGRP3. In addition to activating Ras, RasGRP3 also activates Rap1, which in some cases can antagonize the function of Ras. We demonstrate that DGK bound to RasGRP3 and inhibited its activation of Rap1 by metabolizing DAG. This inhibition consequently affected Ras signaling. We tested the physiological consequence of deleting DGK by crossing wild-type or DGK -deficient mice with mice carrying a v-Ha-Ras transgene, and then we assessed tumor formation. We observed significantly fewer tumors in DGK -deficient mice. Because Rap1 can antagonize the function of Ras, our data are consistent with a model in which DGK regulates RasGRP3 with a predominant effect on Rap1 activity. Additionally, we found that DGK , which is structurally similar to DGK , inhibited RasGRPs 1, 3, and 4 and predominantly affected Ras signaling. Thus, type IV DGKs regulate RasGRPs, but the downstream effects differ depending on the DGK. D iacylglycerol (DAG) is a potent activator of several signaling proteins, many of which, when abnormally active, can contribute to the initiation or promotion of cancer (1, 2). Several enzymes can metabolize signaling DAG, but the major route is thought to be by its phosphorylation, a reaction that produces phosphatidic acid and is catalyzed by the DAG kinases (DGKs) (reviewed in ref. 2). DAG exerts its effects by activating classical and novel protein kinase C isoforms, as well as other proteins including the Ras guanyl nucleotide-releasing proteins (RasGRPs) (reviewed in refs. 3-5). Although the transforming effects of DAG have been attributed to activation of PKCs, identification of the RasGRP family suggested that DAG could also transform cells by directly activating RasGRPs, which in turn could lead to excess Ras signaling. The four known RasGRP proteins are RasGRP1 [calcium DAG guanine exchange factor II (CalDAG-GEFII)], RasGRP2 (CalDAG-GEFI), RasGRP3 (CalDAG-GEFIII), and RasGRP4 (reviewed in ref. 5). Each RasGRP activates either Ras or Rap1, except RasGRP3, which is unique because it facilitates exchange for both .Activating mutations in Ras are found in a number of tumors (reviewed in ref. 11). Using a mouse model, Chin et al. (12) showed that Ras expression was an absolute requirement for melanoma tumor maintenance, and other studies have demonstrated a role for Ras in metastasis (reviewed in ref. 13). Together, these data clearly show that abnormally active Ras contributes to the maintenance and progression of many types of cancer.Rap1-dependent signaling is not a...

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“…A new class of GEFs, expressed mainly in brain and T cells (5,6), is composed of at least four members: 1) RasGRP, the first member characterized as a GEF for Ras (7); 2) CalDAGI or RasGRP2, which possesses GEF activity for N-Ras, K-Ras, and Rap1 (8); 3) CalDAGIII or Ras-GRP3, which can activate both Ras and Rap 1 (9); 4) RasGRP4, recently discovered, has been shown to activate H-Ras in a cation-dependent manner (10,11). All these GRP members have a pair of atypical EF-hands (a calcium-binding motif), and the C1 domain, which represents a signature motif that is involved in the recognition of phorbol ester and diacylglycerol (DAG) (12)(13)(14).…”

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confidence: 99%