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

Yuichi Aiba, Masatsugu Oh-Hora, Shigeki Kiyonaka, Yayoi Kimura, Atsushi Hijikata, Yasuo Mori, Tomohiro Kurosaki

    Research output: Contribution to journalArticle

    62 Citations (Scopus)

    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-γ2 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.

    Original languageEnglish
    Pages (from-to)16612-16617
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume101
    Issue number47
    DOIs
    Publication statusPublished - Nov 23 2004

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    B-Lymphocytes
    Phosphorylation
    Diglycerides
    Type C Phospholipases
    Lymphocyte Activation
    Nucleotides
    Pharmacology
    Mutation

    All Science Journal Classification (ASJC) codes

    • General

    Cite this

    Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated Ras activation. / Aiba, Yuichi; Oh-Hora, Masatsugu; Kiyonaka, Shigeki; Kimura, Yayoi; Hijikata, Atsushi; Mori, Yasuo; Kurosaki, Tomohiro.

    In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 47, 23.11.2004, p. 16612-16617.

    Research output: Contribution to journalArticle

    Aiba, Yuichi ; Oh-Hora, Masatsugu ; Kiyonaka, Shigeki ; Kimura, Yayoi ; Hijikata, Atsushi ; Mori, Yasuo ; Kurosaki, Tomohiro. / Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated Ras activation. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 47. pp. 16612-16617.
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    AU - Aiba, Yuichi

    AU - Oh-Hora, Masatsugu

    AU - Kiyonaka, Shigeki

    AU - Kimura, Yayoi

    AU - Hijikata, Atsushi

    AU - Mori, Yasuo

    AU - Kurosaki, Tomohiro

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    AB - 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-γ2 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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