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Cited by 80Protein Kinase Regulation and GTPase SignalingCellular transport and secretionSphingolipid Metabolism and Signaling

Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated Ras activation

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Aiba, Yuichi, Oh-hora, Masatsugu, Kiyonaka, Shigeki, Kimura, Yayoi, Hijikata, Atsushi, Mori, Yasuo, Kurosaki, Tomohiro·2004·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0407468101PMC PMC528733
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Abstract

The Ras signaling pathway plays a critical role in B lymphocyte development and activation, but its activation mechanism has not been well understood. At least one mode of Ras regulation in B cells involves a Ras-guanyl nucleotide exchange factor, RasGRP3. We demonstrate here that RasGRP3 undergoes phosphorylation at Thr-133 upon B cell receptor cross-linking, thereby resulting in its activation. Deletion of phospholipase C-gamma2 or pharmacological interference with conventional PKCs resulted in marked reduction in both Thr-133 phosphorylation and Ras activation. Moreover, mutation of Thr-133 in RasGRP3 alone severely impaired its ability to activate Ras in B cell receptor signaling. Hence, our data suggest that PKC, after being activated by diacylglycerol, phosphorylates RasGRP3, thereby contributing to its full activation.

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  • Several biochemical pathways and processes negatively regulate PLCγ2 activity and calcium flux after BCR engagement, including RasGRP3, Bam32, Dok-3 with Grb2, Themis2, BLNK, and SFRP2.

    “Several biochemical pathways and processes were shown to negatively regulate PLCγ2 activity and the resulting calcium flux after BCR engagement. These include RasGRP3 (39, 40), Bam32 (41), hematopoietic adaptor protein Dok-3 (downstream of kinase-3) with Grb2 (42), Themis2, an adaptor protein with no known enzymatic activity, via constitutive binding to Lyn, Grb2, and PLCγ2 to mediate its function”

    From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [40]

    The Abstract and Results describe PLC-γ2 as upstream of RasGRP3 activation after BCR engagement; they do not report that RasGRP3 negatively regulates PLC-γ2 or calcium flux. Searches for RasGRP3-mediated inhibition of PLC-γ2 and calcium flux found no passage addressing that claim. The cited paper does not address the other listed regulators. (LLM, conf=0.76)

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Authors
Aiba, Y., Oh-hora, M., Kiyonaka, S., Kimura, Y., Hijikata, A., Mori, Y., & Kurosaki, T.
Affiliations
  • Kansai Medical University (JP)
  • Laboratories of Lymphocyte Differentiation and Immunogenomics, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan; Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi 570-8506, Japan; and Laboratory of Molecular Biology, Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 606-8501, Japan
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2004-11-15
Volume
101
Issue
47
Pages
16612-16617
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0407468101
PMC
PMC528733
OpenAlex
W1973189139
Cited by
79
References
35
Citations by year
2024: 1 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 4 · 2015: 3 · 2014: 4 · 2013: 5 · 2012: 1
FWCI
2.61
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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 › Sphingolipid Metabolism and Signaling
Keywords
RasGRP3, B cell receptor signaling, Ras activation, PLCγ2, protein kinase C, diacylglycerol, B cell activation
MeSH terms
Amino Acid Sequence, Animals, Cell Line, Chickens, Cross-Linking Reagents, Humans, Models, Molecular, Mutation, Type C Phospholipases, Phosphorylation, Protein Conformation, Protein Kinase C, Receptors, Antigen, B-Cell, Recombinant Proteins, Threonine, Signal Transduction, Sequence Homology, Amino Acid, ras Proteins, Guanine Nucleotide Exchange Factors, Phospholipase C gamma, Static Electricity

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