The DOI matches its Crossref record; 56 of the 56 references it cites were found in a registry or an index.
Identification of Guanine Nucleotide Exchange Factors (GEFs) for the Rap1 GTPase
Open accessAbstract
Although the Ras subfamily of GTPases consists of approximately 20 members, only a limited number of guanine nucleotide exchange factors (GEFs) that couple extracellular stimuli to Ras protein activation have been identified. Furthermore, no novel downstream effectors have been identified for the M-Ras/R-Ras3 GTPase. Here we report the identification and characterization of three Ras family GEFs that are most abundantly expressed in brain. Two of these GEFs, MR-GEF (M-Ras-regulated GEF, KIAA0277) and PDZ-GEF (KIAA0313) bound specifically to nucleotide-free Rap1 and Rap1/Rap2, respectively. Both proteins functioned as Rap1 GEFs in vivo. A third GEF, GRP3 (KIAA0846), activated both Ras and Rap1 and shared significant sequence homology with the calcium- and diacylglycerol-activated GEFs, GRP1 and GRP2. Similarly to previously identified Rap GEFs, C3G and Smg GDS, each of the newly identified exchange factors promoted the activation of Elk-1 in the LNCaP prostate tumor cell line where B-Raf can couple Rap1 to the extracellular receptor-activated kinase cascade. MR-GEF and PDZ-GEF both contain a region immediately N-terminal to their catalytic domains that share sequence homology with Ras-associating or RalGDS/AF6 homology (RA) domains. By searching for in vitro interaction with Ras-GTP proteins, PDZ-GEF specifically bound to Rap1A- and Rap2B-GTP, whereas MR-GEF bound to M-Ras-GTP. C-terminally truncated MR-GEF, lacking the GEF catalytic domain, retained its ability to bind M-Ras-GTP, suggesting that the RA domain is important for this interaction. Co-immunoprecipitation studies confirmed the interaction of M-Ras-GTP with MR-GEF in vivo. In addition, a constitutively active M-Ras(71L) mutant inhibited the ability of MR-GEF to promote Rap1A activation in a dose-dependent manner. These data suggest that M-Ras may inhibit Rap1 in order to elicit its biological effects.
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“it also uniquely associates with SHOC2 and PPI1C40 as well as certain RapGEFs52,53.”
From Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance (2024) · cites this paper as [52]
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Cites
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Sorted by citations
Rap1 signalling: adhering to new models
Bos, J. L., de Rooij, J., & Reedquist, K. A. (2001) · Nature Reviews Molecular Cell Biology · doi:10.1038/35073073 · Cited by 625
Margarit, S. M., Sondermann, H., Hall, B. E., Nagar, B., Hoelz, A., Pirruccello, M., Bar‐Sagi, D., & Kuriyan, J. (2003) · Cell · doi:10.1016/s0092-8674(03)00149-1 · Cited by 486
Crk family adaptors–signalling complex formation and biological roles
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Castro, A. F., Rebhun, J. F., Clark, G. J., & Quilliam, L. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300226200 · Cited by 381
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Metadata
- Authors
- Rebhun, J. F., Castro, A. F., & Quilliam, L. A.
- Affiliations
- Indiana University Indianapolis (US)
- Corresponding author
- Quilliam, Lawrence A.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-11
- Volume
- 275
- Issue
- 45
- Pages
- 34901-34908
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2033334272
- Cited by
- 164
- References
- 56
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 8 · 2018: 7 · 2017: 4 · 2016: 7 · 2015: 2 · 2014: 6 · 2013: 3 · 2012: 13
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- guanine nucleotide exchange factor, Rap1 GTPase, M-Ras, Ras family GTPases, Rap1A, Rap2B, Elk-1, BRAF, GTPase activation, brain
- MeSH terms
- Amino Acid Sequence, Brain, Calcium, Cell Line, Diglycerides, DNA-Binding Proteins, Dose-Response Relationship, Drug, Enzyme Activation, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Plasmids, Precipitin Tests, Protein Binding, Proto-Oncogene Proteins, Tissue Distribution, Transcription Factors, Tumor Cells, Cultured, Blotting, Northern, Mutagenesis, Sequence Homology, Amino Acid, Protein Structure, Tertiary, DNA, Complementary, Receptors, Cytoplasmic and Nuclear, Proto-Oncogene Proteins c-raf, Catalytic Domain, Guanine Nucleotide Exchange Factors, ras Guanine Nucleotide Exchange Factors, rap GTP-Binding Proteins, rap1 GTP-Binding Proteins, ets-Domain Protein Elk-1
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