1997
DOI: 10.1074/jbc.272.34.20990
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14-3-3 ζ Negatively Regulates Raf-1 Activity by Interactions with the Raf-1 Cysteine-rich Domain

Abstract: Although Raf-1 is a critical effector of Ras signaling and transformation, the mechanism by which Ras promotes Raf-1 activation is complex and remains poorly understood. We recently reported that Ras interaction with the Raf-1 cysteine-rich domain (Raf-CRD, residues 139 -184) may be required for Raf-1 activation. The Raf-CRD is located in the NH 2 -terminal negative regulatory domain of Raf-1 and is highly homologous to cysteinerich domains found in protein kinase C family members. Recent studies indicate that… Show more

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Cited by 126 publications
(144 citation statements)
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“…In contrast, other data suggest that 14-3-3 may inhibit Raf-1 activation. For example, a Raf-1 mutation that abrogates binding of 14-3-3 to the isolated CRD domain in vitro renders Raf-1 transforming in vivo (Clark et al, 1997), and an S259A mutation that abrogates binding of 14-3-3 to the N-terminus of Raf-1 (Rommel et al, 1996) increases Raf-1 kinase activity (Rommel et al, 1997). In a recent study, we have reconciled some of these disparate observations.…”
Section: Introductionmentioning
confidence: 68%
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“…In contrast, other data suggest that 14-3-3 may inhibit Raf-1 activation. For example, a Raf-1 mutation that abrogates binding of 14-3-3 to the isolated CRD domain in vitro renders Raf-1 transforming in vivo (Clark et al, 1997), and an S259A mutation that abrogates binding of 14-3-3 to the N-terminus of Raf-1 (Rommel et al, 1996) increases Raf-1 kinase activity (Rommel et al, 1997). In a recent study, we have reconciled some of these disparate observations.…”
Section: Introductionmentioning
confidence: 68%
“…The isolated RafCRD binds to 14-3-3 in vitro (Clark et al, 1997) and C165S,C168S mutations that disrupt the zinc ®nger within the RafCRD (RafCC/SS), have been reported to abrogate all binding of 14-3-3 to full-length Raf-1 in vitro (Michaud et al, 1995). However, when anti-Flag immunoprecipitates prepared from the NP-40 soluble fraction of COS cells expressing FlagRafCC/SS were immunoblotted for 14-3-3 we found a substantial amount of 14-3-3 was present, comparable to the amount of 14-3-3 in immunoprecipitates prepared from cells expressing wild type FlagRaf (Figure 1).…”
Section: Resultsmentioning
confidence: 99%
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“…While the RBD provides a high a nity site for Ras-GTP, the zinc binding region interacts with Rasfarnesyl and is critical for the activation of the protein kinase (Chuang et al, 1994;Hu et al, 1995;Luo et al, 1997). Association with Ras dislodges 14.3.3 from CR2, possibly opening up the molecule for activation by further modi®cation (Clark et al, 1997;Rommel et al, 1996).…”
Section: Introductionmentioning
confidence: 99%