The Phosphotyrosine Interaction Domain of SHC Recognizes Tyrosine-phosphorylated NPXY Motif

Songyang, Zhou; Margolis, Benjamin; Chaudhuri, Manas; Shoelson, S.E.; Cantley, Lewis C.

doi:10.1074/jbc.270.25.14863

Cited by 173 publications

(113 citation statements)

References 26 publications

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“…Fe65 Interacts with APP in a Phosphorylation-independent Fashion, and the Interaction Motif Is Longer than the ⌽XNPXY Consensus-It was clearly demonstrated by competition experiments that Shc binds, through its PID/PTB domain, to activated growth factor receptor in a tyrosine phosphorylation-dependent manner (18). Synthetic peptides covering different regions of the APP intracellular domain have been tested for their ability to compete for the binding between Fe65 and APP.…”

Section: Resultsmentioning

confidence: 99%

“…However, Fe65 possesses at least two unique characteristics: (i) although all the known members of the PID/PTB family contain only one PID/ PTB element (13), Fe65 is an exception, because its sequence interacting with APP shows two consecutive PID/PTB domains; and (ii) although the Tyr present in the consensus sequence of all the growth factor receptors must be phosphorylated to allow the binding to the PID/PTB domain of Shc and IRS-1 (18), no experimental result supports the possibility that the Tyr of the consensus motif present in the intracellular domain of APP can be phosphorylated.…”

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confidence: 99%

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Interaction of the Phosphotyrosine Interaction/Phosphotyrosine Binding-related Domains of Fe65 with Wild-type and Mutant Alzheimer's β-Amyloid Precursor Proteins

Zambrano

Buxbaum

Minopoli

et al. 1997

Journal of Biological Chemistry

142

124

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The ␤-amyloid precursor protein (APP) 1 is an integral membrane protein from which the ␤-amyloid peptide is generated. The ␤-amyloid peptide forms the extracellular insoluble aggregates characteristic of Alzheimer's disease. The function of APP and the regulation of the proteolytic events generating the ␤-amyloid peptide are still unknown. APP was expected to be involved in signal transduction processes, because of its transmembrane topology. Three main isoforms of APP exist, generated by alternative splicing (APP 770 , APP 751 , and APP 695 ) and all possessing the same intracellular domain (reviewed in Ref.1). Although little is known about the putative extracellular ligand(s) for APP, several results describe the interaction of its intracellular domain with other proteins. These include the interaction with the heterotrimeric G protein Go (2), a 59-kDa ubiquitously expressed protein named APP-BP1 (3), the X11 protein (4), the neuron-abundant Fe65 protein, and an Fe65-like protein (4 -6). It was shown that intact APP binds to oligomeric Go protein and that the intracellular region of APP spanning residues 657-676 activates Go (2, 7). Furthermore, the interaction of APP with a monoclonal antibody directed against its extracellular domain mimics a ligand-receptor binding that triggers Go activation (7). APP-BP1 interacts both in vitro and in vivo with the carboxyl-terminal region of APP, which represents its intracellular domain. This protein is homologous to the product of the Arabidopsis auxin resistance gene AXR1 and to a Caenorabditis elegans protein of unknown function (3).The Fe65 gene is mainly expressed in the neurons of specific regions of the mammalian nervous system (8, 9) and encodes a protein containing two different types of protein-protein interaction domains: the WW domain (reviewed in Ref. 10) and the phosphotyrosine interaction/phosphotyrosine binding (PID/ PTB) domain (reviewed in Ref. 11). The latter was found in the oncoprotein Shc (12, 13), in its relatives , in other apparently unrelated proteins, such as Numb, X11, and Dab (15), and in insulin receptor substrate 1 (IRS-1) and 17). The PID/PTB domains interact with phosphotyrosine residues located in the intracellular domains of growth factor receptors, such as EGF-R, trkA, and plateletderived growth factor receptor in the case of Shc (13) and insulin receptor and interleukin 4 receptor in the case of IRS-1 (16). In contrast, the Fe65 region containing the two PID/PTB domains was demonstrated to interact with the intracellular domain of APP (5).All the PID/PTB domains present in the Shc family, IRS-1, and Fe65 interact with intracellular regions of membrane proteins containing the consensus motif ⌽XNPXY (where ⌽ is hydrophobic and X is any amino acid). However, Fe65 possesses at least two unique characteristics: (i) although all the known members of the PID/PTB family contain only one PID/ PTB element (13), Fe65 is an exception, because its sequence interacting with APP shows two consecutive PID/PTB domains; and (ii) although the Tyr prese...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Interaction of the Phosphotyrosine Interaction/Phosphotyrosine Binding-related Domains of Fe65 with Wild-type and Mutant Alzheimer's β-Amyloid Precursor Proteins

Zambrano

Buxbaum

Minopoli

et al. 1997

Journal of Biological Chemistry

142

124

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“…The PTB domain of Shc recognizes tyrosine-phosphorylated peptides in which residues amino terminal to the phosphorylated tyrosine determine binding speci®city (Songyang et al, 1995;van der Geer et al, 1995). The Shc PTB domain has been shown to bind directly to N-P-X-pY sequence motifs in the cytoplasmic domains of the EGFR (Blaikie et al, 1994), TrkA (Dikic et al, 1995), RET (Lorenzo et al, 1997) and the IL-2Rb chain (Ravichandran et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells

1999

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“…These PTB domains are functionally similar to SH2 domains in the sense that they bind directly to short peptide motifs in a fashion that is regulated by phosphorylation of the ligand, and depends on residues¯anking the phosphorylation site (Songyang et al, 1995). However, the structures of the Shc and IRS-1 PTB domains, and the mechanisms by which they recognize speci®c phosphopeptides, are quite di erent from those displayed by SH2 domains (Eck et al, 1996;Zhou et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site

1999

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Shc and IRS-1 (and their relatives) are cytoplasmic docking proteins that possess phosphotyrosine-binding (PTB) domains, through which they bind speci®c activated receptor tyrosine kinases (RTK). The subsequent phosphorylation of Shc or IRS-1 creates binding sites for the SH2 domains of multiple signaling proteins, leading to the activation of intracellular biochemical pathways. The PTB domains of Shc and IRS-1 both recognize autophosphorylation sites in RTKs with the consensus sequence NPXpY, but show distinct abilities to bind stably to RTKs such as the TrkA nerve growth factor receptor and the insulin receptor. In vitro analysis has suggested that residues N-terminal to the NPXpY motif may determine the a nity with which phosphopeptide ligands are recognized by the Shc and IRS-1 PTB domains. Unlike IRS-1, the Shc PTB domain binds poorly to the insulin-receptor (IR) b subunit in vitro, owing to its low a nity for the NPXpY autophosphorylation site at Tyr 960 of the IR. As a consequence, Shc does not bind stably to the activated IR in cells. We show that substitution of Ser 955, ®ve residues Nterminal to the Tyr 960 autophosphorylation site (the 75 position), with Ile alters the target speci®city of the IR such that it stably associates with Shc in insulinstimulated cells. A triple substitution of the 75, 78 and 79 residues relative to Tyr 960 of the IR to the corresponding amino acids found in the Shc PTB domain binding site of TrkA results in even stronger binding of the IR to Shc in vivo. The variant IRs with enhanced ability to bind Shc showed an increased ability to activate the MAPK pathway in response to insulin stimulation. These results demonstrate that subtle di erences in residues N-terminal to NPXpY autophosphorylation sites determine the ability of RTKs to bind speci®c PTB domain proteins in vivo, and thus modify the signaling properties of activated receptors.

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The Phosphotyrosine Interaction Domain of SHC Recognizes Tyrosine-phosphorylated NPXY Motif

Cited by 173 publications

References 26 publications

Interaction of the Phosphotyrosine Interaction/Phosphotyrosine Binding-related Domains of Fe65 with Wild-type and Mutant Alzheimer's β-Amyloid Precursor Proteins

Interaction of the Phosphotyrosine Interaction/Phosphotyrosine Binding-related Domains of Fe65 with Wild-type and Mutant Alzheimer's β-Amyloid Precursor Proteins

Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells

Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site

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