Spred is a sprouty-related suppressor of Ras signalling

Toru Wakioka, Atsuo Sasaki, Reiko Kato, Takanori Shouda, Akira Matsumoto, Kanta Miyoshi, Makoto Tsuneoka, Setsuro Komiya, Roland Baron, Akihiko Yoshimura

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308 Citations (Scopus)

Abstract

Cellular proliferation, and differentiation of cells in response to extracellular signals, are controlled by the signal transduction pathway of Ras, Raf and MAP (mitogen-activated protein) kinase. The mechanisms that regulate this pathway are not well known. Here we describe two structurally similar tyrosine kinase substrates, Spred-1 and Spred-2. These two proteins contain a cysteine-rich domain related to Sprouty (the SPR domain) at the carboxy terminus. In Drosophila, Sprouty inhibits the signalling by receptors of fibroblast growth factor (FGF) and epidermal growth factor (EGF) by suppressing the MAP kinase pathway. Like Sprouty, Spred inhibited growth-factor-mediated activation of MAP kinase. The Ras-MAP kinase pathway is essential in the differentiation of neuronal cells and myocytes. Expression of a dominant negative form of Spred and Spred-antibody microinjection revealed that endogenous Spred regulates differentiation in these types of cells. Spred constitutively associated with Ras but did not prevent activation of Ras or membrane translocation of Raf. Instead, Spred inhibited the activation of MAP kinase by suppressing phosphorylation and activation of Raf. Spred may represent a class of proteins that modulate Ras-Raf interaction and MAP kinase signalling.

Original languageEnglish
Pages (from-to)647-651
Number of pages5
JournalNature
Volume412
Issue number6847
DOIs
Publication statusPublished - 2001 Aug 9
Externally publishedYes

ASJC Scopus subject areas

  • General

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    Wakioka, T., Sasaki, A., Kato, R., Shouda, T., Matsumoto, A., Miyoshi, K., Tsuneoka, M., Komiya, S., Baron, R., & Yoshimura, A. (2001). Spred is a sprouty-related suppressor of Ras signalling. Nature, 412(6847), 647-651. https://doi.org/10.1038/35088082