Spred is a Sprouty-related suppressor of Ras signalling

Cellular proliferation, and differentiation of cells in response to extrace llular signals, are controlled by the signal transduction pathway of Ras, R af 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 contai n a cysteine-rich domain related to Sprouty (the SPR domain) at the carboxy terminus. In Drosophila, Sprouty inhibits the signalling by receptors of f ibroblast growth factor (FGF) and epidermal growth factor (EGF) by suppress ing the MAP kinase pathway(2-7). Like Sprouty, Spred inhibited growth-facto r-mediated activation of MAP kinase. The Ras-MAP kinase pathway is essentia l in the differentiation of neuronal cells and myocytes. Expression of a do minant negative form of Spred and Spred-antibody microinjection revealed th at endogenous Spred regulates differentiation in these types of cells. Spre d constitutively associated with Ras but did not prevent activation of Ras or membrane translocation of Raf. Instead, Spred inhibited the activation o f MAP kinase by suppressing phosphorylation and activation of Raf. Spred ma y represent a class of proteins that modulate Ras-Raf interaction and MAP k inase signalling.