Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1998-04-22
2000-02-22
Russel, Jeffrey E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530321, 530326, 530327, 530328, 530329, 530345, A61K 3808, A61K 3810, A61K 3812, C07K 706, C07K 708
Patent
active
060280530
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The invention relates to peptides which interfere with the interaction of a phosphotyrosine-binding (PTB) domain containing protein with a PTB domain binding site; and, uses of the peptides.
BACKGROUND OF THE INVENTION
Shc is a member of a group of proteins that are collectively known as adaptor proteins. These adaptors, which are composed of protein-protein interaction domains such as the Src-homology 2 (SH2) and Src-homology 3 (SH3) domains, mediate protein-protein interactions that are important for signal transduction downstream of growth factor and cytokine receptors (Pawson, 1995). Shc has been shown to bind to a wide variety of activated growth factor and cytokine receptors. Shc was cloned from a human cDNA library in a screen for SH2 domain-containing proteins (Pelicci et al., 1992); Shc homologs in mouse (mShc) and drosophila (dShc) have also been cloned (Lai et al., 1995). Three proteins are encoded by the shc gene that differ from each other only in their amino-terminus (Lai et al., 1995; Pelicci et al., 1992). Overexpression of Shc results in cellular transformation of NIH3T3 fibroblasts and Ras-dependent neurite outgrowth of PC12 cells, suggesting that Shc plays an important role in signal transduction leading to DNA synthesis and cell division or differentiation (Pelicci et al., 1992; Rozakis-Adcock et al., 1992).
Shc contains an amino-terminal phosphotyrosine-binding (PTB) domain, a central Pro-rich region that contains the principal tyrosine phosphorylation site at Tyr 317, and an SH2 domain at its carboxy-terminus. The PTB domain, which is highly conserved in Shc-related proteins, was recently identified based on its ability to bind to phosphotyrosine-containing proteins (Blaikie et al., 1994; Kavanaugh and Williams, 1994; van der Geer et al., 1995). It recognizes phosphotyrosine present within the sequence Asn-Pro-X-P.Tyr and differs from SH2 domains that recognize phosphotyrosine in the context of carboxy-terminal residues (Kavanaugh et al., 1995; van der Geer et al., 1995). The Shc SH2 domain recognizes phosphotyrosine within the sequence P.Tyr-Glu/Leu/Ile/Tyr-X-Leu/Ile/Met (Songyang et al., 1994).
Shc becomes phosphorylated on tyrosine following stimulation with a wide variety of growth factors and cytokines (Burns et al., 1993; Crowe et al., 1994; Cutler et al., 1993; Lanfrancone et al., 1995; Pelicci et al., 1992; Pronk et al., 1993; Ravichandran et al., 1993; Segatto et al., 1993; Yokote et al., 1994). Tyrosine phosphorylation of Shc is essential for its interaction with the Grb2-Sos complex, which may provide a mechanism for Ras activation (Buday and Downward, 1993; Crowe et al., 1994; Egan et al., 1993; Gale et al., 1993; Li et al., 1993; Rozakis-Adcock et al., 1993; Rozakis-Adcock et al., 1992; Salcini et al., 1994). Shc has also been shown to bind physically to activated growth factor and cytokine receptors. Several growth factor receptors that had previously been shown to bind to Shc upon activation contain tyrosine phosphorylation sites present within the sequence Asn-Pro-X-P.Tyr, consistent with the notion that it is the PTB domain that mediates Shc's interaction with these proteins (Campbell et al., 1994; van der Geer and Pawson, 1995). Furthermore, the Shc PTB domain has been shown to bind to the activated nerve growth factor (NGF) receptor, the activated epidermal growth factor (EGF) receptor, polyoma middle T antigen, and to a 145 kDa protein that becomes phosphorylated on tyrosine in PDGF stimulated cells (Blaikie et al., 1994; Kavanaugh and Williams, 1994; van der Geer et al., 1995). The NGF receptor contains a single Shc-binding site at Tyr 490 that is present within a Asn-Pro-X-Tyr motif (Obermeier et al., 1994; Stephens et al., 1994). NGF receptors that have been mutated at Tyr 490 lack the ability to interact with Shc in vivo or with the PTB domain in vitro (Stephens et al., 1994). Phosphotyrosine-containing peptides based on the Shc binding site in middle T antigen, which is also present within an Asn-Pro-X-P.Tyr motif, compete with the N
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Gish Gerald
Pawson Anthony
Toma Kazunori
van der Geer Peter
Wiley Sandra
Asahi Chemical Industry Co., Ltd.
Mount Sinai Hospital Corporation
Russel Jeffrey E.
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