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

Parker, Fabienne; Maurier, Florence; Delumeau, Isabelle; Duchesne, Marc; Faucher, Didier; Debussche, Laurent; Dugue, A; Schweighoffer, Fabien; Tocqué, Bruno

doi:10.1128/mcb.16.6.2561

Cited by 196 publications

(252 citation statements)

References 62 publications

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“…A current working model proposes that Ras-GTP binding to the COOH-terminal catalytic domain would expose the protein-ligand binding motifs present in the NH 2 -terminus, and the subsequent association of components with the NH 2 -terminus would activate a signaling function. The identi®cation of other p120 GAP-binding proteins in addition to p190 Rho GAP, (e.g., p62 dok , G3BP) provide support for such a scenario (Settleman et al, 1992;Yamanashi and Baltimore, 1997;Ellis et al, 1990;Parker et al, 1996).…”

Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 92%

Increasing complexity of Ras signaling

et al. 1998

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The initial discovery that ras genes endowed retroviruses with potent carcinogenic properties and the subsequent determination that mutated ras genes were present in a wide variety of human cancers, prompted a strong suspicion that the growth-promoting actions of mutated Ras proteins contribute to their aberrant regulation of growth stimulatory signaling pathways. In 1993, a remarkable convergence of experimental observations from genetic analyses of Drosophila, S. cerevisiae and C. elegans as well as biochemical and biological studies in mammalian cells came together to de®ne a clear role for Ras in signal transduction. What emerged was an elegant linear signaling pathway where Ras functions as a relay switch that is positioned downstream of cell surface receptor tyrosine kinases and upstream of a cytoplasmic cascade of kinases that included the mitogen-activated protein kinases (MAPKs). Activated MAPKs in turn regulated the activities of nuclear transcription factors. Thus, a signaling cascade where every component between the cell surface and the nucleus was de®ned and conserved in worms,¯ies and man. This was a remarkable achievement in our e orts to appreciate how the aberrant function of Ras proteins may contribute to the malignant growth properties of the cancer cell. However, the identi®cation of this pathway has proven to be just the beginning, rather than the culmination, of our understanding of Ras in signal transduction. Instead, we now appreciate that this simple linear pathway represents but a minor component of a very complex signaling circuitry. Ras signaling has emerged to involve a complex array of signaling pathways, where cross-talk, feedback loops, branch points and multi-component signaling complexes are recurring themes. The simplest concept of a signaling cascade, where each component simply relays the same message to the next, is clearly not the case. In this review, we summarize our current understanding of Ras signal transduction with an emphasis on new complexities associated with the recognition and/or activation of cellular e ectors, and the diverse array of signaling pathways mediated by interaction between Ras and Ras-subfamily proteins with multiple e ectors.

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Section: Ras Mediates Its Actions Through Interaction With Multiple Ementioning

confidence: 92%

Increasing complexity of Ras signaling

et al. 1998

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“…This led to the identification of the 62-kDa species as G3BP2 (AF051311), a protein homologous to G3BP (rasGAP SH3-binding protein; Ref. 68) that we renamed G3BP1. G3BP1 and G3BP2 proteins present 59% identity and display an identical overall molecular organization with an N-terminal domain homologous to the NTF2 protein, a protein involved in nucleocytoplasmic transport (NTF2-like domain; 27% identity and 50% homology with NTF2), followed by an acidic domain (composed of 40% acidic residues), a domain containing five PXXP motifs in G3BP2 and one in G3BP1 (PXXP domain) and a C-terminal domain containing another PXXP motif, RNP2, and RNP1 consensus sequences as well as an RGG-rich region that is therefore related to an RNA-binding domain.…”

Section: Resultsmentioning

confidence: 99%

IκBα and IκBα/NF-κB Complexes Are Retained in the Cytoplasm through Interaction with a Novel Partner, RasGAP SH3-binding Protein 2

Prigent¹,

Barlat²,

Langen³

et al. 2000

Journal of Biological Chemistry

105

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IB␣ inhibits the transcriptional activity of NF-B both in the cytoplasm by preventing the nuclear translocation of NF-B and in the nucleus where it dissociates NF-B from DNA and transports it back to the cytoplasm. Cytoplasmic localization of inactive NF-B/IB␣ complexes is controlled by mutual masking of nuclear import sequences of NF-B p65 and IB␣ and active CRM1-mediated nuclear export. Here, we describe an additional mechanism accounting for the cytoplasmic anchoring of IB␣ or NF-B/IB␣ complexes. The N-terminal domain of IB␣ contains a sequence responsible for the cytoplasmic retention of IB␣ that is specifically recognized by G3BP2, a cytoplasmic protein that interacts with both IB␣ and IB␣/NF-B complexes. G3BP2 is composed of an N-terminal domain homologous to the NTF2 protein, followed by an acidic domain sufficient for the interaction with the IB␣ cytoplasmic retention sequence, a region containing five PXXP motifs and a C-terminal domain containing RNA-binding motifs. Overexpression of G3BP2 directly promotes retention of IB␣ in the cytoplasm, indicating that subcellular distribution of IB␣ and NF-B/IB␣ complexes likely results from a equilibrium between nuclear import, nuclear export, and cytoplasmic retention. The molecular organization of G3BP2 suggests that this putative scaffold protein might connect the NF-B signal transduction cascade with cellular functions such as nuclear transport or RNA metabolism.Rel/NF-B transcription factors play a major role in inducible expression of a number of cellular genes involved in immune, inflammatory, and anti-apoptotic responses (1-3). Human NF-B is composed of a homo-or heterodimer of proteins that belong to the multigene family of transcription factors comprising p50, p52, p65/RelA, c-Rel, and RelB (4 -12). The prototypical NF-B is a heterodimeric p50/p65 molecule. Each member of NF-B/Rel family of proteins contains a Rel homology domain that is responsible for nuclear translocation, dimerization, and sequence-specific DNA binding. In most unstimulated cells, NF-B is retained in an inactive form in the cytoplasm through its association with the IB inhibitor proteins (13-16). IBs also belong to a multigene family of proteins including IB␣, IB␤, IB⑀, Bcl-3, and also the C-terminal domains of p50 and p52 precursors (p105 and p100, respectively) that in isolation are known as IB␥ and IB␦, respectively (17-25). Members of the IB family contain multiple conserved ankyrin repeat domains that interact with NF-B factors such that their nuclear localization sequences (NLS) 1 are masked, leading to cytoplasmic retention of the complex. IB proteins are also characterized by their ability to inhibit NF-B DNA binding activity.IB␣ is composed of a surface-exposed N-terminal domain, a central region containing six ankyrin repeat domains, and a highly acidic C-terminal domain. Upon stimulation of cells with appropriate signals such as tumor necrosis factor or interleukin 1, a signaling cascade is initiated leading to activation of two IB␣ kinases, IKK-1 and IKK-2, which phosph...

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“…2B). The sequence between amino acids 224 and 246 conforms to a consensus P⌿XXSPLLPXPXP sequence, where ⌿ indicates a hydrophobic amino acid, found in the following four known SH3 domainbinding proteins: CR16, a protein encoded by a brain-specific mRNA regulated by glucocorticoids (15); SH3 BP2, a protein that binds to the Src, Nck, Grb-2, and Abl SH3 domains (16); the Ras-GAP SH3 binding protein (17); and Abi-2, a protein cloned based on its ability to bind with high affinity to the SH3 domain of Abl (18). It should be noted, however, that the proline-rich domains of SH3 BP-2 and Abi-2 that are homologous to Sirm are not the same as those implicated in Abl binding (16,18 , and ir Ϫ/Ϫ mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of sirm, a Novel Insulin-regulated SH3 Binding Protein That Associates with Grb-2 and FYN

Salvatore¹,

R.²,

Kido³

et al. 1998

Journal of Biological Chemistry

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We have previously developed a mouse model of insulin-resistant diabetes by targeted inactivation of the insulin receptor gene. During studies of gene expression in livers of insulin receptor-deficient mice, we identified a novel cDNA, which we have termed sirm (Son of Insulin Receptor Mutant mice). sirm is largely, albeit not exclusively, expressed in insulin-responsive tissues. Insulin is a potent modulator of sirm expression, and sirm mRNA levels correlate with tissue sensitivity to insulin. The product of the sirm gene is a serine/threonine-rich protein with several proline-rich motifs and an NPNY motif, conforming to the consensus sequence recognized by the phosphotyrosine binding domains of insulin receptor substrate and Shc proteins. However, Sirm bears no extended homologies with other known proteins. Based on the sequences of the proline-rich domains, we sought to determine whether Sirm binds to the SH3 domains of FYN and Grb-2. We demonstrate here that Sirm binds to FYN and Grb-2 in 3T3-L1 adipocytes and that insulin treatment results in the dissociation of the Sirm⅐FYN and Sirm⅐Grb-2 complexes. We also show that Sirm is a substrate for the kinase activity of FYN in vitro. Based on the patterns of expression of sirm, its regulation by insulin, and the interactions with molecules in the insulin signaling pathway, we surmise that Sirm plays a role in modulating tissue sensitivity to insulin.

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

Cited by 196 publications

References 62 publications

Increasing complexity of Ras signaling

Increasing complexity of Ras signaling

IκBα and IκBα/NF-κB Complexes Are Retained in the Cytoplasm through Interaction with a Novel Partner, RasGAP SH3-binding Protein 2

Identification of sirm, a Novel Insulin-regulated SH3 Binding Protein That Associates with Grb-2 and FYN

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