Mammalian Sprouty4 Suppresses Ras-Independent ERK Activation by Binding to Raf1

Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis

“…This study showed that C-terminal CR domain plays an essential role in PKC suppression, Ca 2 þ mobilization, as well as IP 3 production. In addition, the CR domain interacts with Raf-1, which inhibits Raf-1 activation (Sasaki et al, 2003). Therefore, the suppression of both PIP 2 breakdown and inhibition of Raf-1 activation by the CR domain seems to be an efficient regulatory mechanism of Sprouty4 for PKC-mediated ERK activation.…”

“…In addition, three Sprouty-related genes, Spreds were identified (Sprouty-related Ena/VASP homology 1 domain-containing proteins) . Mammalian Sproutys and Spreds inhibit growth factor-induced cellular responses by inhibiting the RTK-dependent ERK signaling pathway (Gross et al, 2001;Impagnatiello et al, 2001;Lee et al, 2001;Sasaki et al, 2001Sasaki et al, , 2003Yigzaw et al, 2001;Hanafusa et al, 2002;Yusoff et al, 2002). Sproutys are considered to be a candidate of anti-oncogenes, as reduced expression of Sproutys has been shown in several cancers Lo et al, 2006).…”

“…It is clear that Spred1 is involved in the suppression of the Ras-ERK pathway in vivo, as a loss-of-function mutation of SPRED1 gene was found in human NCFC syndrome, which is caused by dysregulation of the RTK/Ras/ERK pathway (Brems et al, 2007). On the other hand, several mechanisms for the Sprouty-mediated inhibition of the RTK/Ras/ERK pathway have been proposed, including the avoidance of Grb2-Sos recruitment (Gross et al, 2001;Hanafusa et al, 2002) or the inhibition of Raf Sasaki et al, 2003).…”

“…Similarly, Sprouty4 inhibits vascular endothelial growth factor (VEGF)-A-induced PKC-mediated ERK activation, whereas Sprouty4 does not inhibit EGF as well as VEGF-C-mediated ERK activation (Sasaki et al, 2001(Sasaki et al, , 2003Taniguchi et al, 2007). Molecular basis for the suppression of the PKC pathway remains to be solved.…”

“…Therefore, the phosphorylation of these N-terminal tyrosine residues seems to be essential for the inhibitory activity of Sproutys on FGF-induced ERK activation (Sasaki et al, 2001;Hanafusa et al, 2002). However, in the case of VEGF-A signaling, the N-terminal region including Y53 of Sprouty4 is not necessary for suppression, whereas the CR domain is indispensable (Sasaki et al, 2003). The Sprouty2 CR domain has been shown to bind to phosphatidylinositol 4,5-biphosphate (PIP 2 ), which is not essential for the suppression of ERK activation .…”