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SHP-1 is a protein-tyrosine phosphatase associated with inhibition of activation pathways in hematopoietic cells. The catalytic activity of SHP-1 is regulated by its two SH2 (Src homology 2) domains; phosphotyrosine peptides that bind to the SH2 domains activate SHP-1. The consensus sequence (I/V)XYXX(L/V) is present in the cytoplasmic tails of several lymphocyte receptors that interact with the second SH2 domain of SHP-1. In several of these receptors, there are two or three occurrences of the motif. Here we show that the conserved hydrophobic amino acid preceding the phosphotyrosine is critical for binding to and activation of SHP-1 by peptides corresponding to sequences from killer cell inhibitory receptors. The interaction of most SH2 domains with phosphopeptides requires only the phosphotyrosine and the three residues downstream of the tyrosine. In contrast, the shortest peptide able to bind or activate SHP-1 also included the two residues upstream of the phosphotyrosine. A biphosphopeptide corresponding to the cytoplasmic tail of a killer cell inhibitory receptor with the potential to interact simultaneously with both SH2 domains of SHP-1 was the most potent activator of SHP-1. The hydrophobic residue upstream of the tyrosine was also critical in the context of the biphosphopeptide. The contribution of a hydrophobic amino acid two residues upstream of the tyrosine in the SHP-1-binding motif may be an important feature that distinguishes inhibitory receptors from those that provide activation signals. SHP-1 is a protein-tyrosine phosphatase associated with inhibition of activation pathways in hematopoietic cells. The catalytic activity of SHP-1 is regulated by its two SH2 (Src homology 2) domains; phosphotyrosine peptides that bind to the SH2 domains activate SHP-1. The consensus sequence (I/V)XYXX(L/V) is present in the cytoplasmic tails of several lymphocyte receptors that interact with the second SH2 domain of SHP-1. In several of these receptors, there are two or three occurrences of the motif. Here we show that the conserved hydrophobic amino acid preceding the phosphotyrosine is critical for binding to and activation of SHP-1 by peptides corresponding to sequences from killer cell inhibitory receptors. The interaction of most SH2 domains with phosphopeptides requires only the phosphotyrosine and the three residues downstream of the tyrosine. In contrast, the shortest peptide able to bind or activate SHP-1 also included the two residues upstream of the phosphotyrosine. A biphosphopeptide corresponding to the cytoplasmic tail of a killer cell inhibitory receptor with the potential to interact simultaneously with both SH2 domains of SHP-1 was the most potent activator of SHP-1. The hydrophobic residue upstream of the tyrosine was also critical in the context of the biphosphopeptide. The contribution of a hydrophobic amino acid two residues upstream of the tyrosine in the SHP-1-binding motif may be an important feature that distinguishes inhibitory receptors from those that provide activation signals. Receptor-mediated activation of cellular responses is often initiated by the activation of tyrosine kinases. The signal is propagated by the sequential recruitment of proteins to the phosphorylated targets of the kinases. SH2 (Srchomology 2) domains are protein modules that specifically bind to phosphotyrosine residues and are found in a variety of proteins such as protein kinases and adapter molecules. A general feature of all SH2 domains is a conserved pocket that binds the phosphotyrosine moiety. The specificity of the interaction between individual SH2 domains and particular phosphoproteins is generally determined by three to six residues following the phosphotyrosine and often incorporates a hydrophobic residue at the third position (reviewed in Ref. 1Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). This specificity is provided by specific pockets that bind the phosphotyrosine and +3 residues as revealed by structural studies of several SH2 domains complexed with phosphopeptides (1Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar).A small family of protein-tyrosine phosphatases contain SH2 domains. This family is composed of mammalian SHP-1 and SHP-2 and theDrosophila homologue of SHP-2, corkscrew. These protein-tyrosine phosphatases are important regulators of many cellular signaling processes (reviewed in Ref. 2Tonks N.K. Neel B.G. Cell. 1996; 87: 365-368Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar). SHP-2 is broadly expressed and is important for activation signals through several different growth factor receptors. In contrast, SHP-1 is expressed predominantly in hematopoietic cells and has been implicated in inhibition of signaling through growth factor, cytokine, and antigen receptors. These protein-tyrosine phosphatases contain two SH2 domains in tandem and a single catalytic domain. The protein-tyrosine phosphatase activity is negatively regulated by the SH2 domains in that their removal or occupancy by phosphopeptides increases the phosphatase activity of the catalytic domain (3Townley R. Shen S.H. Banville D. Ramachandran C. Biochemistry. 1993; 32: 13414-13418Crossref PubMed Scopus (77) Google Scholar, 4Lechleider R.J. Sugimoto S. Bennett A.M. Kashishian A.S. Cooper J.A. Shoelson S.E. Walsh C.T. Neel B.G. 1993; Full Text PDF PubMed Google Scholar, Full Text PDF PubMed Google Scholar, S. Shoelson S.E. Neel B.G. Walsh C.T. Full Text PDF PubMed Google Scholar, S. Walsh C.T. Shoelson S.E. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, Shen S.H. 1995; PubMed Scopus Google Scholar). The SH2 domains of SHP-1 and SHP-2 are to to SH2 domains with their the SH2 domains of and Shoelson S.E. T. T. S. R.J. Neel B.G. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). is of particular to the specificity of these SH2 domains both the and activation of these binding sequences for SH2 domains been with and sequence The SH2 domain SH2 SH2 receptor killer cell inhibitory SH2 SH2 receptor killer cell inhibitory of SHP-2 binds to Shoelson S.E. T. T. S. R.J. Neel B.G. Cell. 1993; Full Text PDF PubMed Scopus Google and the domain of SHP-1 binds to Shoelson S.E. T. T. R. D. S. Cell. PubMed Scopus Google Scholar). The of these was by the of sequences in several receptors that bind to the domain of such as and and receptors. to a sequence to the domains of both SHP-1 and SHP-2, the second SH2 domain of SHP-1 is to a for hydrophobic residues at and +3 Shoelson S.E. T. T. R. D. S. Cell. PubMed Scopus Google to the binding studies that only residues downstream of the we the motif by sequence of inhibitory receptors to SHP-1 A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). These the lymphocyte receptors R.J. 1995; PubMed Scopus Google and D. 1995; PubMed Scopus Google and the family of killer cell inhibitory receptors expressed in killer and A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). from and been to bind to the domain of SHP-1 A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. 1995; PubMed Scopus Google has been to interact with the domain Shen S.H. 1996; PubMed Scopus Google Scholar). The motif is also found in A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, T. C. 1993; PubMed Scopus Google a associated with a receptor to be in inhibition of killer cells 1996; Full Text Full Text PDF PubMed Scopus Google and in a with inhibitory potential expressed in cells S. 1996; PubMed Scopus Google and in killer cells S. Google Scholar). A was found in A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google family of inhibitory receptors that are expressed in killer cells 1993; PubMed Scopus Google Scholar). from interact with the SH2 domains of both SHP-1 and SHP-2 D. R. 1996; Google Scholar). The inhibitory receptors expressed in killer and as as the inhibitory receptors and also the sequence upstream of the the specificity of the interaction of receptors with the (I/V)XYXX(L/V) motif and SHP-1. SHP-1 was implicated in the inhibitory signals of of a in the signaling in cells from D. 1995; PubMed Scopus Google Scholar). has been that in cells of SHP-1 and with the phosphatase also an SH2 domain S. Nature. 1996; PubMed Scopus Google Scholar). SHP-1 as a for the inhibitory signals by A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google and SHP-1 with the receptor tyrosine A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. R. 1996; Google Scholar, A.M. 1996; PubMed Scopus Google Scholar, 1996; PubMed Scopus Google Scholar). that the of SHP-1 its by the of a different protein with was important in the inhibitory In studies with cells show the of with a protein that in to SHP-1 as as several proteins 1996; PubMed Scopus Google Scholar). we proteins that bind to phosphotyrosine peptides corresponding to cytoplasmic tail sequences of and the amino in the consensus sequence (I/V)XYXX(L/V) are important for interaction with we the specificity of the interaction of sequences motif with SHP-1 and the contribution of these residues to the activation and binding of SHP-1. The a critical for the amino acid two residues upstream of the tyrosine in SHP-1 binding and corresponding to or a single protein in lymphocyte that with SHP-1. These the that a of SHP-1 by specifically with SHP-1 A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A.M. 1996; Full Text PDF PubMed Scopus Google Scholar). In contrast, a corresponding to the cytoplasmic tail two of with SHP-1 and with the phosphatase These the of inhibition by SHP-1 or D. 1995; PubMed Scopus Google Scholar, S. Nature. 1996; PubMed Scopus Google Scholar). these that the consensus motif that are important for binding and activation of peptides corresponding to the sequence that the consensus sequence was to most of the activity of the The peptide a for the upstream residues in the peptide to interact with SHP-1. with of that position is the most position upstream as only with hydrophobic residues at position able to activate the SHP-1 protein-tyrosine also binding of the sequence to the that is in the peptide binding to SH2 domain. The of upstream residues in a motif is of are to SH2 bind phosphotyrosine in a pocket by conserved amino The specificity of domain binding is by amino upstream of the the motif (reviewed in Ref. 1Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). The motif for activation of SHP-1 is in that residues both of the of residue was in the context of the biphosphopeptide This is a peptide is a to the of the In the peptide included of the amino of the cytoplasmic peptides a in PubMed Scopus Google is that the upstream residues a for the interaction of the peptide and the SH2 domain. such an is was able to activate of the SH2 domains of the protein-tyrosine phosphatase SHP-2 complexed with phosphopeptides position may be in peptide binding to the SH2 domains of SHP-1. These revealed that the residues to to the phosphotyrosine D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. Shoelson S.E. Nature. 1996; PubMed Scopus Google Scholar). In to a peptide complexed with the SH2 domain of Shoelson S.E. D. Cell. 1993; Full Text PDF PubMed Scopus Google residue is in with the SH2 domains of SHP-2 D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. Shoelson S.E. Nature. 1996; PubMed Scopus Google Scholar). their sequence to SHP-2, the SH2 domains of SHP-1 are to the feature of an to SH2 domains. The peptide from the growth factor receptor with SHP-2 has a at position In the the of the the all the peptides that bind to SHP-2 contain a residue at position the at position in the growth factor receptor peptide has been to be important for binding and activation of SHP-2 Ramachandran C. Biochemistry. 1995; PubMed Scopus Google Scholar). is that the interaction with the tyrosine and the of residue an contribution for an interaction may be in general for the binding of peptides to the domain of SHP-1. The phosphotyrosine position in the SH2 domains of SHP-2 is different in SH2 domains D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google and may to the for the a hydrophobic pocket in the domain of present in SHP-2, at position to the binding of peptides to the SHP-1 domain. these for a of interaction with position and for the sequences from the lymphocyte receptors that a hydrophobic residue at position there are for and peptides with SHP-2, these are D. R. 1996; Google Scholar).A for peptide binding for many of the residues downstream of a phosphotyrosine. In the structural studies of SHP-2, of both peptides with the protein for +3 and D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google Scholar). a may the of peptides to In of the upstream of activity to the downstream of and in of SHP-1 This that and residues downstream of the tyrosine. The of consensus at of these in the sequences that bind that and residues that are to the the two residues between the tyrosine and the are residues position +3 also been implicated for binding of phosphopeptides to the domain of SHP-2 A.M. R.J. Neel B.G. Shoelson S.E. Full Text PDF PubMed Google of SH2 domain is with of residue is A specific interaction of the peptides with the domain was is to that the domain is the only domain. the of the biphosphopeptide to such activation as with the that both and both SH2 domains are in the The interaction with the domain may be of and is in the two are a interaction is of activation by has been for SHP-2 S. Walsh C.T. Shoelson S.E. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). with at position the of the biphosphopeptide to activate provided that the consensus residues are critical amino for binding and activation of SHP-1. at position the sequences of inhibitory receptors from the sequences in the receptor activation of receptors. This motif from the binding of SH2 domains by the of upstream Receptor-mediated activation of cellular responses is often initiated by the activation of tyrosine kinases. The signal is propagated by the sequential recruitment of proteins to the phosphorylated targets of the kinases. SH2 (Srchomology 2) domains are protein modules that specifically bind to phosphotyrosine residues and are found in a variety of proteins such as protein kinases and adapter molecules. A general feature of all SH2 domains is a conserved pocket that binds the phosphotyrosine moiety. The specificity of the interaction between individual SH2 domains and particular phosphoproteins is generally determined by three to six residues following the phosphotyrosine and often incorporates a hydrophobic residue at the third position (reviewed in Ref. 1Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). This specificity is provided by specific pockets that bind the phosphotyrosine and +3 residues as revealed by structural studies of several SH2 domains complexed with phosphopeptides (1Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). A small family of protein-tyrosine phosphatases contain SH2 domains. This family is composed of mammalian SHP-1 and SHP-2 and theDrosophila homologue of SHP-2, corkscrew. These protein-tyrosine phosphatases are important regulators of many cellular signaling processes (reviewed in Ref. 2Tonks N.K. Neel B.G. Cell. 1996; 87: 365-368Abstract Full Text Full Text PDF PubMed Scopus (489) Google Scholar). SHP-2 is broadly expressed and is important for activation signals through several different growth factor receptors. In contrast, SHP-1 is expressed predominantly in hematopoietic cells and has been implicated in inhibition of signaling through growth factor, cytokine, and antigen receptors. These protein-tyrosine phosphatases contain two SH2 domains in tandem and a single catalytic domain. The protein-tyrosine phosphatase activity is negatively regulated by the SH2 domains in that their removal or occupancy by phosphopeptides increases the phosphatase activity of the catalytic domain (3Townley R. Shen S.H. Banville D. Ramachandran C. Biochemistry. 1993; 32: 13414-13418Crossref PubMed Scopus (77) Google Scholar, 4Lechleider R.J. Sugimoto S. Bennett A.M. Kashishian A.S. Cooper J.A. Shoelson S.E. Walsh C.T. Neel B.G. 1993; Full Text PDF PubMed Google Scholar, Full Text PDF PubMed Google Scholar, S. Shoelson S.E. Neel B.G. Walsh C.T. Full Text PDF PubMed Google Scholar, S. Walsh C.T. Shoelson S.E. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, Shen S.H. 1995; PubMed Scopus Google Scholar). The SH2 domains of SHP-1 and SHP-2 are to to SH2 domains with their the SH2 domains of and Shoelson S.E. T. T. S. R.J. Neel B.G. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). is of particular to the specificity of these SH2 domains both the and activation of these The binding sequences for SH2 domains been with and sequence The SH2 domain SH2 SH2 receptor killer cell inhibitory SH2 SH2 receptor killer cell inhibitory of SHP-2 binds to Shoelson S.E. T. T. S. R.J. Neel B.G. Cell. 1993; Full Text PDF PubMed Scopus Google and the domain of SHP-1 binds to Shoelson S.E. T. T. R. D. S. Cell. PubMed Scopus Google Scholar). The of these was by the of sequences in several receptors that bind to the domain of such as and and receptors. to a sequence to the domains of both SHP-1 and SHP-2, the second SH2 domain of SHP-1 is to a for hydrophobic residues at and +3 Shoelson S.E. T. T. R. D. S. Cell. PubMed Scopus Google Scholar). In to the binding studies that only residues downstream of the we the motif by sequence of inhibitory receptors to SHP-1 A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). These the lymphocyte receptors R.J. 1995; PubMed Scopus Google and D. 1995; PubMed Scopus Google and the family of killer cell inhibitory receptors expressed in killer and A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). from and been to bind to the domain of SHP-1 A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. 1995; PubMed Scopus Google has been to interact with the domain Shen S.H. 1996; PubMed Scopus Google Scholar). The motif is also found in A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, T. C. 1993; PubMed Scopus Google a associated with a receptor to be in inhibition of killer cells 1996; Full Text Full Text PDF PubMed Scopus Google and in a with inhibitory potential expressed in cells S. 1996; PubMed Scopus Google and in killer cells S. Google Scholar). A was found in A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google family of inhibitory receptors that are expressed in killer cells 1993; PubMed Scopus Google Scholar). from interact with the SH2 domains of both SHP-1 and SHP-2 D. R. 1996; Google Scholar). The inhibitory receptors expressed in killer and as as the inhibitory receptors and also the sequence upstream of the tyrosine. the specificity of the interaction of receptors with the (I/V)XYXX(L/V) motif and SHP-1. SHP-1 was implicated in the inhibitory signals of of a in the signaling in cells from D. 1995; PubMed Scopus Google Scholar). has been that in cells of SHP-1 and with the phosphatase also an SH2 domain S. Nature. 1996; PubMed Scopus Google Scholar). SHP-1 as a for the inhibitory signals by A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google and SHP-1 with the receptor tyrosine A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, D. R. 1996; Google Scholar, A.M. 1996; PubMed Scopus Google Scholar, 1996; PubMed Scopus Google Scholar). that the of SHP-1 its by the of a different protein with was important in the inhibitory In studies with cells show the of with a protein that in to SHP-1 as as several proteins 1996; PubMed Scopus Google Scholar). we proteins that bind to phosphotyrosine peptides corresponding to cytoplasmic tail sequences of and the amino in the consensus sequence (I/V)XYXX(L/V) are important for interaction with we the specificity of the interaction of sequences motif with SHP-1 and the contribution of these residues to the activation and binding of SHP-1. The a critical for the amino acid two residues upstream of the tyrosine in SHP-1 binding and corresponding to or a single protein in lymphocyte that with SHP-1. These the that a of SHP-1 by specifically with SHP-1 A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A.M. 1996; Full Text PDF PubMed Scopus Google Scholar). In contrast, a corresponding to the cytoplasmic tail two of with SHP-1 and with the phosphatase These the of inhibition by SHP-1 or D. 1995; PubMed Scopus Google Scholar, S. Nature. 1996; PubMed Scopus Google Scholar). these that the consensus motif that are important for binding and activation of peptides corresponding to the sequence that the consensus sequence was to most of the activity of the The peptide a for the upstream residues in the peptide to interact with SHP-1. with of that position is the most position upstream as only with hydrophobic residues at position able to activate the SHP-1 protein-tyrosine also binding of the sequence to the that is in the peptide binding to SH2 domain. The of upstream residues in a motif is of are to SH2 bind phosphotyrosine in a pocket by conserved amino The specificity of domain binding is by amino upstream of the the motif (reviewed in Ref. 1Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). The motif for activation of SHP-1 is in that residues both of the of residue was in the context of the biphosphopeptide This is a peptide is a to the of the In the peptide included of the amino of the cytoplasmic peptides a in PubMed Scopus Google is that the upstream residues a for the interaction of the peptide and the SH2 domain. such an is was able to activate of the SH2 domains of the protein-tyrosine phosphatase SHP-2 complexed with phosphopeptides position may be in peptide binding to the SH2 domains of SHP-1. These revealed that the residues to to the phosphotyrosine D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. Shoelson S.E. Nature. 1996; PubMed Scopus Google Scholar). In to a peptide complexed with the SH2 domain of Shoelson S.E. D. Cell. 1993; Full Text PDF PubMed Scopus Google residue is in with the SH2 domains of SHP-2 D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. Shoelson S.E. Nature. 1996; PubMed Scopus Google Scholar). their sequence to SHP-2, the SH2 domains of SHP-1 are to the feature of an to SH2 domains. The peptide from the growth factor receptor with SHP-2 has a at position In the the of the the all the peptides that bind to SHP-2 contain a residue at position the at position in the growth factor receptor peptide has been to be important for binding and activation of SHP-2 Ramachandran C. Biochemistry. 1995; PubMed Scopus Google Scholar). is that the interaction with the tyrosine and the of residue an contribution for an interaction may be in general for the binding of peptides to the domain of SHP-1. The phosphotyrosine position in the SH2 domains of SHP-2 is different in SH2 domains D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google and may to the for the a hydrophobic pocket in the domain of present in SHP-2, at position to the binding of peptides to the SHP-1 domain. these for a of interaction with position and for the sequences from the lymphocyte receptors that a hydrophobic residue at position there are for and peptides with SHP-2, these are D. R. 1996; Google Scholar).A for peptide binding for many of the residues downstream of a phosphotyrosine. In the structural studies of SHP-2, of both peptides with the protein for +3 and D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google Scholar). a may the of peptides to In of the upstream of activity to the downstream of and in of SHP-1 This that and residues downstream of the tyrosine. The of consensus at of these in the sequences that bind that and residues that are to the the two residues between the tyrosine and the are residues position +3 also been implicated for binding of phosphopeptides to the domain of SHP-2 A.M. R.J. Neel B.G. Shoelson S.E. Full Text PDF PubMed Google of SH2 domain is with of residue is A specific interaction of the peptides with the domain was is to that the domain is the only domain. the of the biphosphopeptide to such activation as with the that both and both SH2 domains are in the The interaction with the domain may be of and is in the two are a interaction is of activation by has been for SHP-2 S. Walsh C.T. Shoelson S.E. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). with at position the of the biphosphopeptide to activate provided that the consensus residues are critical amino for binding and activation of SHP-1. at position the sequences of inhibitory receptors from the sequences in the receptor activation of receptors. This motif from the binding of SH2 domains by the of upstream corresponding to or a single protein in lymphocyte that with SHP-1. These the that a of SHP-1 by specifically with SHP-1 A.M. S. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A.M. 1996; Full Text PDF PubMed Scopus Google Scholar). In contrast, a corresponding to the cytoplasmic tail two of with SHP-1 and with the phosphatase These the of inhibition by SHP-1 or D. 1995; PubMed Scopus Google Scholar, S. Nature. 1996; PubMed Scopus Google Scholar). these that the consensus motif that are important for binding and activation of peptides corresponding to the sequence that the consensus sequence was to most of the activity of the The peptide a for the upstream residues in the peptide to interact with SHP-1. with of that position is the most position upstream as only with hydrophobic residues at position able to activate the SHP-1 protein-tyrosine also binding of the sequence to the that is in the peptide binding to SH2 domain. The of upstream residues in a motif is of are to SH2 bind phosphotyrosine in a pocket by conserved amino The specificity of domain binding is by amino upstream of the the motif (reviewed in Ref. 1Pawson T. Nature. 1995; 373: 573-580Crossref PubMed Scopus (2217) Google Scholar). The motif for activation of SHP-1 is in that residues both of the tyrosine. The of residue was in the context of the biphosphopeptide This is a peptide is a to the of the In the peptide included of the amino of the cytoplasmic peptides a in PubMed Scopus Google is that the upstream residues a for the interaction of the peptide and the SH2 domain. such an is was able to activate SHP-1. The of the SH2 domains of the protein-tyrosine phosphatase SHP-2 complexed with phosphopeptides position may be in peptide binding to the SH2 domains of SHP-1. These revealed that the residues to to the phosphotyrosine D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. Shoelson S.E. Nature. 1996; PubMed Scopus Google Scholar). In to a peptide complexed with the SH2 domain of Shoelson S.E. D. Cell. 1993; Full Text PDF PubMed Scopus Google residue is in with the SH2 domains of SHP-2 D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google Scholar, S. T. Shoelson S.E. Nature. 1996; PubMed Scopus Google Scholar). their sequence to SHP-2, the SH2 domains of SHP-1 are to the feature of an to SH2 domains. The peptide from the growth factor receptor with SHP-2 has a at position In the the of the the all the peptides that bind to SHP-2 contain a residue at position the at position in the growth factor receptor peptide has been to be important for binding and activation of SHP-2 Ramachandran C. Biochemistry. 1995; PubMed Scopus Google Scholar). is that the interaction with the tyrosine and the of residue an contribution for an interaction may be in general for the binding of peptides to the domain of SHP-1. The phosphotyrosine position in the SH2 domains of SHP-2 is different in SH2 domains D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google and may to the for the a hydrophobic pocket in the domain of present in SHP-2, at position to the binding of peptides to the SHP-1 domain. these for a of interaction with position and for the sequences from the lymphocyte receptors that a hydrophobic residue at position there are for and peptides with SHP-2, these are D. R. 1996; Google Scholar). A for peptide binding for many of the residues downstream of a phosphotyrosine. In the structural studies of SHP-2, of both peptides with the protein for +3 and D. S. Shoelson S.E. Full Text Full Text PDF PubMed Scopus Google Scholar). a may the of peptides to In of the upstream of activity to the downstream of and in of SHP-1 This that and residues downstream of the tyrosine. The of consensus at of these in the sequences that bind that and residues that are to the the two residues between the tyrosine and the are residues position +3 also been implicated for binding of phosphopeptides to the domain of SHP-2 A.M. R.J. Neel B.G. Shoelson S.E. Full Text PDF PubMed Google Scholar). The of SH2 domain is with of residue is A specific interaction of the peptides with the domain was is to that the domain is the only domain. the of the biphosphopeptide to such activation as with the that both and both SH2 domains are in the The interaction with the domain may be of and is in the two are a interaction is of activation by has been for SHP-2 S. Walsh C.T. Shoelson S.E. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). with at position the of the biphosphopeptide to activate SHP-1. provided that the consensus residues are critical amino for binding and activation of SHP-1. at position the sequences of inhibitory receptors from the sequences in the receptor activation of receptors. This motif from the binding of SH2 domains by the of upstream for and D. and for the
Burshtyn et al. (Thu,) studied this question.