Implication of GAP in Ras-dependent transactivation of a polyoma enhancer sequence

Schweighoffer, Fabien; Barlat, I; Chevallier-Multon, M C; Tocqué, Bruno

doi:10.1126/science.1317056

Cited by 49 publications

(26 citation statements)

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“…Type I GAP inhibited the wt H-Ras induction of a reporter gene regulated by AP-1 promoter elements and also reduced serum-stimulated DNA synthesis, a process which is thought to depend upon endogenous wt Ras (24,29). These data support the hypothesis that type I GAP can act as a negative regulator of wt Ras, although it may also act as an effector of Ras (12,17,27 While type I GAP has been isolated primarily from the cytosolic fraction of quiescent cells (23), it can be speculated that GAP associates with Ras at the membrane at some time in the regulatory cycle, thereby lending support for this possibility. Alternatively, the two forms of GAP may have different half-lives in cells, which could also give rise to the observed cellular activities.…”

Section: Discussionsupporting

confidence: 66%

Differential regulation of cellular activities by GTPase-activating protein and NF1.

Al-Alawi¹,

Xu²,

White³

et al. 1993

Mol. Cell. Biol.

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Section: Discussionsupporting

confidence: 66%

Differential regulation of cellular activities by GTPase-activating protein and NF1.

Al-Alawi¹,

Xu²,

White³

et al. 1993

Mol. Cell. Biol.

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“…This is in accordance with several studies showing that the effect of the prototypic GAP protein p120 as a negative regulator of Ras is commenced by protein-protein interactions through its various noncatalytic domains (Martin et al, 1992;Schweighoffer et al, 1992;Clark et al, 1993Clark et al, , 1997Drugan et al, 2000). This allosteric effect of the noncatalytic domains on the GAP activity was demonstrated when overexpression of sequences from the NH 2 -terminal region of p120 GAP (N-GAP), excluding the Ras-interacting catalytic domain, modulated Ras signaling.…”

Section: Egf Induces Pkc-dependent Phosphorylation Of the N-terminussupporting

confidence: 91%

Phosphorylation of neurofibromin by PKC is a possible molecular switch in EGF receptor signaling in neural cells

Mangoura

Sun

et al. 2005

Oncogene

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Children with neurofibromatosis (NF1) typically develop central nervous system (CNS) abnormalities, including aberrant proliferation of astrocytes and formation of benign astrocytomas. The NF1 gene encodes neurofibromin, a Ras-GAP, highly expressed in developing neural cells; the mechanism of regulation of neurofibromin as a Ras-GAP, remains however unknown. We now show that, in response to EGF, neurofibromin is in vivo phosphorylated on serine residues by PKC-a, in human, rat, and avian CNS cells and cell lines. EGF-induced PKC phosphorylation was prominent in the cysteine/serine-rich domain (CSRD) of neurofibromin, which lies in the Nterminus and upstream of the Ras-GAP domain (GRD), and this modification significantly increased the association of neurofibromin with actin in co-immunoprecipitations. In addition, we show that Ras activation in response to EGF was significantly lowered when C62B cells overexpressed a construct encoding both CSRD þ GRD. Moreover, when PKC-a was downregulated, the Ras-GAP activity of CSRD þ GRD was significantly diminished, whereas overexpressed GRD alone acted as a weaker GAP and in a PKC-independent manner. Most importantly, functional Ras inhibition and EGF signaling shifts were established at the single cell level in C6-derived cell lines stably overexpressing CSRD þ GRD, when transient co-overexpression of Ras and PKC-depletion prior to stimulation with EGF-induced mitosis. Taken together, these data provide the first evidence of a functional, allosteric regulation of GRD by CSRD, which requires neurofibromin phosphorylation by PKC and association with the actin cytoskeleton. Our data may suggest a novel mechanism for regulating biological responses to EGF and provide a new aspect for the understanding of the aberrant proliferation seen in the CNS of children with NF1.

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“…One attractive candidate for a Ras effector protein, other than the Raf kinase (19), is GAP (47,63). Ras binds GAP via its COOH-terminal domain (GAP-C) (27), while the NH 2 terminal region appears to be essential for triggering downstream signals (6,28).…”

mentioning

confidence: 99%

A Ras-GTPase-Activating Protein SH3-Domain-Binding Protein

Parker

Maurier

Delumeau

et al. 1996

Molecular and Cellular Biology

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196

235

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We report the purification of a Ras-GTPase-activating protein (GAP)-binding protein, G3BP, a ubiquitously expressed cytosolic 68-kDa protein that coimmunoprecipitates with GAP. G3BP physically associates with the SH3 domain of GAP, which previously had been shown to be essential for Ras signaling. The G3BP cDNA revealed that G3BP is a novel 466-amino-acid protein that shares several features with heterogeneous nuclear RNA-binding proteins, including ribonucleoprotein (RNP) motifs RNP1 and RNP2, an RG-rich domain, and acidic sequences. Recombinant G3BP binds effectively to the GAP SH3 domain G3BP coimmunoprecipitates with GAP only when cells are in a proliferating state, suggesting a recruitment of a GAP-G3BP complex when Ras is in its activated conformation.

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Implication of GAP in Ras-dependent transactivation of a polyoma enhancer sequence

Cited by 49 publications

References 0 publications

Differential regulation of cellular activities by GTPase-activating protein and NF1.

Differential regulation of cellular activities by GTPase-activating protein and NF1.

Phosphorylation of neurofibromin by PKC is a possible molecular switch in EGF receptor signaling in neural cells

A Ras-GTPase-Activating Protein SH3-Domain-Binding Protein

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