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 and Akihiko Yoshimura ()
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Toru Wakioka: Medical Institute of Bioregulation, Kyushu University
Atsuo Sasaki: Medical Institute of Bioregulation, Kyushu University
Reiko Kato: Medical Institute of Bioregulation, Kyushu University
Takanori Shouda: Medical Institute of Bioregulation, Kyushu University
Akira Matsumoto: Medical Institute of Bioregulation, Kyushu University
Kanta Miyoshi: Medical Institute of Bioregulation, Kyushu University
Makoto Tsuneoka: Institute of Life Science, Kurume University
Setsuro Komiya: Faculty of Medicine, Kagoshima University
Roland Baron: Yale University School of Medicine
Akihiko Yoshimura: Medical Institute of Bioregulation, Kyushu University

Nature, 2001, vol. 412, issue 6847, 647-651

Abstract: 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 pathway2,3,4,5,6,7. 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.

Date: 2001
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DOI: 10.1038/35088082

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