Mutational Analysis of the SRC Homology 2 Domain Protein-tyrosine Phosphatase Corkscrew

The SRC homology 2 (SH2) domain protein-tyrosine phosphatase, Corkscrew (CSW) is required for signaling by receptor tyrosine kinases, including the Sevenless receptor tyrosine kinase (SEV), which directs Drosophila R7 photoreceptor cell development. To investigate the role of the different domains of CSW, we constructed domain-specific csw mutations and assayed their effects on CSW function. Our results indicate that CSW SH2 domain function is essential, but either CSW SH2 domain can fulfill this requirement. We also found that CSW and activated SEV are associatedin vivo in a manner that does not require either CSW SH2 domain function or tyrosine phosphorylation of SEV. In contrast, the interaction between CSW and Daughter of Sevenless, a CSW substrate, is dependent on SH2 domain function. These results suggest that the role of the CSW SH2 domains during SEV signaling is to bind Daughter of Sevenless rather than activated SEV. We also found that although CSW protein-tyrosine phosphatase activity is required for full CSW function, a catalytically inactive CSW is capable of providing partial function. In addition, we found that deletion of either the CSW protein- tyrosine phosphatase insert or the entire CSW carboxyl terminus, which includes a conserved DRK/GRB2 SH2 domain binding sequence, does not abolish CSW function. The SRC homology 2 (SH2) domain protein-tyrosine phosphatase, Corkscrew (CSW) is required for signaling by receptor tyrosine kinases, including the Sevenless receptor tyrosine kinase (SEV), which directs Drosophila R7 photoreceptor cell development. To investigate the role of the different domains of CSW, we constructed domain-specific csw mutations and assayed their effects on CSW function. Our results indicate that CSW SH2 domain function is essential, but either CSW SH2 domain can fulfill this requirement. We also found that CSW and activated SEV are associatedin vivo in a manner that does not require either CSW SH2 domain function or tyrosine phosphorylation of SEV. In contrast, the interaction between CSW and Daughter of Sevenless, a CSW substrate, is dependent on SH2 domain function. These results suggest that the role of the CSW SH2 domains during SEV signaling is to bind Daughter of Sevenless rather than activated SEV. We also found that although CSW protein-tyrosine phosphatase activity is required for full CSW function, a catalytically inactive CSW is capable of providing partial function. In addition, we found that deletion of either the CSW protein- tyrosine phosphatase insert or the entire CSW carboxyl terminus, which includes a conserved DRK/GRB2 SH2 domain binding sequence, does not abolish CSW function. Receptor tyrosine kinases (RTKs) 1The abbreviations used are: RTK, receptor-tyrosine kinase; SH2, SRC homology 2; CSW, corkscrew; PTP, protein-tyrosine phosphatase; PDGF, platelet-derived growth factor; DOS, Daughter of Sevenless.1The abbreviations used are: RTK, receptor-tyrosine kinase; SH2, SRC homology 2; CSW, corkscrew; PTP, protein-tyrosine phosphatase; PDGF, platelet-derived growth factor; DOS, Daughter of Sevenless. regulate cellular growth and differentiation in response to extracellular signals. The binding of a specific ligand to the extracellular domain of an RTK leads to a well characterized series of biochemical events, including RTK dimerization, activation of the cytoplasmic tyrosine kinase domain, and phosphorylation of the RTK on specific tyrosine residues (reviewed in Ref. 1van der Geer P. Hunter T. Lindberg R.A. Annu. Rev. Cell Biol. 1994; 10: 251-337Crossref PubMed Scopus (1232) Google Scholar). The activated and phosphorylated RTK then regulates key cellular target proteins. Frequently, these targets contain either SRC homology 2 (SH2) domains or phosphotyrosine binding domains that bind to specific phosphorylated tyrosine residues of the RTK. The recruitment of such SH2- and phosphotyrosine binding domain-containing proteins regulates their function and leads to the activation of important intracellular signaling pathways. For example, the interaction of the SH2 domain-containing protein GRB2 with activated RTKs leads to the stimulation of the RAS pathways (2McCormick F. Curr. Opin. Genet. Dev. 1994; 4: 71-76Crossref PubMed Scopus (208) Google Scholar, 3Egan S.E. Weinberg R.A. Nature. 1993; 365: 781-783Crossref PubMed Scopus (523) Google Scholar). Among the key signaling proteins, the function of which is required during RTK signaling, is a class of protein-tyrosine phosphatases that includes SHP2 in mammals and Corkscrew (CSW) in Drosophila(reviewed in Ref. 4Neel B.G. Tonks N.K. Curr. Opin. Cell Biol. 1997; 9: 193-204Crossref PubMed Scopus (731) Google Scholar). In addition to their protein-tyrosine phosphatase (PTP) domains, these proteins are characterized by the presence of two SH2 domains at their amino terminus and a poorly conserved carboxyl-terminal “tail” region. In addition, CSW contains a domain of approximately 150 amino acids that interrupts its PTP domain and is not present in SHP2 (5Perkins L.A. Larsen I. Perrimon N. Cell. 1992; 70: 225-236Abstract Full Text PDF PubMed Scopus (328) Google Scholar). The first evidence that SHP2/CSW proteins were important for RTK signaling came from the identification of CSW as a maternally contributed, positively acting component during signaling by the Drosophila TORSO RTK (5Perkins L.A. Larsen I. Perrimon N. Cell. 1992; 70: 225-236Abstract Full Text PDF PubMed Scopus (328) Google Scholar). Subsequent studies have implicated CSW in signaling by several other Drosophila RTKs including SEV and the Drosophila epidermal growth factor receptor (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google Scholar, 7Perkins L.A. Johnson M.R. Melnick M.B. Perrimon N. Dev. Biol. 1996; 180: 63-81Crossref PubMed Scopus (100) Google Scholar). In vertebrates, SHP2 has been shown to participate in signaling by the epidermal growth factor, PDGF, fibroblast growth factor, and insulin receptors (reviewed in Refs. 4Neel B.G. Tonks N.K. Curr. Opin. Cell Biol. 1997; 9: 193-204Crossref PubMed Scopus (731) Google Scholar and 8Streuli M. Curr. Opin. Cell Biol. 1996; 8: 182-188Crossref PubMed Scopus (164) Google Scholar). Two potential mechanisms for the action of SHP2/CSW during RTK signaling have been proposed. In the case of certain RTKs, such as the PDGF receptor, RTK autophosphorylation creates binding sites for the SH2 domains of SHP2 (9Bennett A.M. Tang T.L. Sugimoto S. Walsh C.T. Neel B.G. Proc. Natl. Acad. S. 1994; PubMed Scopus Google Scholar, R. Cell Biol. 1994; PubMed Google Scholar). to receptor, SHP2 phosphorylated at a tyrosine in its region. SHP2 can then by the SH2 domain of The recruitment of GRB2 to the is to to the activation of the RAS signaling of signaling by the SEV RTK in Drosophila have to an for CSW action during RTK signaling (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google Scholar, R. J.D. T. Simon M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The activation of SEV differentiation of the R7 photoreceptor cell Refs. and der Dev. Scholar, M.A. Dev. Biol. 1994; PubMed Scopus Google Scholar, Annu. Rev. 1994; PubMed Scopus Google Scholar). In the R7 CSW as a component of the signaling by SEV (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google Scholar). have that CSW function is required in the R7 cell activated of RAS and are used to the SEV signaling These have that although CSW in RAS CSW also a role either of activation or in a signaling that in with the to the role of during RTK signaling has been to for their phosphatase CSW substrate, the Daughter of Sevenless protein as a protein in a with a catalytically inactive of CSW R. J.D. T. Simon M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). contains an homology domain and is to the of proteins that includes and T. P. P. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The of mutations that the has that is a component of the SEV R. J.D. T. Simon M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, T. P. P. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). these biochemical and studies have to the that by CSW during SEV for SHP2 in have also to the identification of a of potential these the protein the PDGF receptor, and several proteins with from to (reviewed in Refs. 4Neel B.G. Tonks N.K. Curr. Opin. Cell Biol. 1997; 9: 193-204Crossref PubMed Scopus (731) Google Scholar and 8Streuli M. Curr. Opin. Cell Biol. 1996; 8: 182-188Crossref PubMed Scopus (164) Google Scholar). In to the role of during RTK signaling, we have of the domains of CSW and their effects on SEV signaling and Drosophila development. In this we evidence that the the PTP domain and at SH2 domain are for CSW function. of the of either or CSW to with and SEV that the in vivo of CSW with SEV is not dependent on either the tyrosine phosphorylation of SEV or the presence of SH2 domains in In contrast, the of and CSW CSW SH2 These results suggest that the role of the CSW SH2 domains is not in binding to SEV but is in the of such as In addition, we found that a deletion of either the CSW PTP insert or the conserved GRB2 binding carboxyl terminus of CSW does not CSW function during signaling by and Drosophila and were The csw csw used in this have been characterized as the csw partial are (5Perkins L.A. Larsen I. Perrimon N. Cell. 1992; 70: 225-236Abstract Full Text PDF PubMed Scopus (328) Google Scholar). and as (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google Scholar). in csw were as (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google Scholar). The to in the SH2 domains of CSW were and for csw by from the the of the CSW PTP domain insert acids and the carboxyl terminus acids were the and the SH2 domains by a in the csw The csw were the which contains a of and P. 8: PubMed Scopus Google Scholar). directs in a of in the including and as well as in were the by used in this were The were by the presence of the in the To for of the with csw from a between the and csw were for at The were for the presence which that the CSW function. To CSW function, the csw from the were with The were during their to of the in the of that the These were then for their to to The of that the CSW to CSW function. To the of on the of to R7 from for the and were and the of R7 and protein were as R. J.D. T. Simon M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The csw and were which from (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google Scholar). The and were M.A. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). The were in either or For of and were at for and then to The used in this were (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google which the carboxyl terminus of acids and The domain contains amino acids of CSW R. J.D. T. Simon M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The csw SH2 domain mutations were as The proteins were on For of DOS, of protein with cell cell that were from Our to the role of of the domains of CSW to domain-specific mutations a that a csw the of a P. 8: PubMed Scopus Google Scholar). directs in a of in the including the photoreceptor and and of the cell In addition, the also of the are at for The were the by and assayed for function. In to for in to at different sites in the several different were for In results were The function of the CSW proteins in The first of a of csw that we in a for mutations that signaling by SEV M.A. Cell. Full Text PDF PubMed Scopus Google Scholar). in of the that the to such as not the protein in vivo CSW function and the of CSW (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google Scholar). The of in the of the and R7 and leads to with that are and (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google of CSW the effects we assayed the signaling of CSW proteins by their in also The of that that CSW function during to in of their (5Perkins L.A. Larsen I. Perrimon N. Cell. 1992; 70: 225-236Abstract Full Text PDF PubMed Scopus (328) Google Scholar, 7Perkins L.A. Johnson M.R. Melnick M.B. Perrimon N. Dev. Biol. 1996; 180: 63-81Crossref PubMed Scopus (100) Google Scholar). used to the proteins CSW function to these in that CSW function. The by the to for a csw in to that were for the but the For these we used the csw csw of these has been characterized as a (5Perkins L.A. Larsen I. Perrimon N. Cell. 1992; 70: 225-236Abstract Full Text PDF PubMed Scopus (328) Google Scholar). The to the in which of the protein to the of In these the csw the were in to that were for but were to by the of the These were then for their of CSW is for TORSO signaling and the of these is a for the of the CSW to function during TORSO signaling (5Perkins L.A. Larsen I. Perrimon N. Cell. 1992; 70: 225-236Abstract Full Text PDF PubMed Scopus (328) Google Scholar). SH2 domains an that is in a conserved T. PubMed Scopus Google Scholar). and studies have shown that this is for the interaction between an SH2 domain and the phosphotyrosine of its target binding Google Scholar). We the of the CSW SH2 domains by the of SH2 domain and to and the of the proteins to function in the mutations in SH2 domains to either the of csw function or to the in the and of R7 photoreceptor by csw were in the of the and for the presence of the R7 photoreceptor were for in a were in the of the and for the presence of the R7 photoreceptor were for These results the of CSW SH2 domain function but not indicate SH2 domains are We this by the function of CSW proteins in which a SH2 domain results were with and In the protein capable of providing CSW function to the of CSW function and of providing CSW function in from the with constructed not These results that of the SH2 proteins capable of providing CSW function to fulfill the of CSW and suggest that the two SH2 domains In to their to function as the or of CSW function during of the SH2 domain proteins at the of indicate that of with CSW function by of its SH2 domains to bind to an or target of The and the proteins than CSW of the binding by the of of the SH2 domain role for the SH2 domains of CSW during SEV signaling is to CSW to bind to activated SEV. studies of the role of SHP2 in signaling by the PDGF and epidermal growth factor receptors has that the SHP2 SH2 domains bind to sites of autophosphorylation on the activated RTKs R. 1993; PubMed Scopus Google Scholar, T. Genet. 1994; 10: Full Text PDF PubMed Scopus Google Scholar, Neel B.G. Biol. 1993; Full Text PDF PubMed Google and that this interaction can to the tyrosine phosphorylation of We the SH2 domains of CSW required to CSW to with activated SEV. We first to SEV and CSW can found in a in not of SEV and of CSW, we used that been to of CSW the of and an activated of SEV the of a of these leads to the of of catalytically and SEV R. J.D. T. Simon M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of were with to SEV. of these by with the presence of CSW a of the CSW the were found in the the results indicate that CSW and SEV can in Drosophila Among the for the of the are during the and the for cellular protein that not in the the of CSW and in CSW not phosphorylated and does not to a target for activated SEV not a catalytically inactive CSW also with and to that the of CSW phosphorylation not to not To investigate CSW and SEV in a manner to that for SHP2 and the PDGF receptor, we the of CSW and on the tyrosine phosphorylation of SEV and the SH2 domains of Two were In the a of that CSW and a catalytically inactive of the were then used to the of CSW found in from and to the of CSW with SEV not different between the of the two cell the of tyrosine phosphorylation of and not These results that the between CSW and SEV is to between CSW SH2 domains and SEV phosphorylation In to the of the SH2 domains of CSW in the interaction with we with from a cell CSW in which the SH2 domains were by as We found that the presence of the SH2 domain mutations not the these results indicate that the presence of CSW SH2 domains is not required for the of CSW and SEV. these results the that CSW and SEV protein rather than with The of an SH2- and CSW and SEV that a role of the SH2 domains of CSW in of CSW function of phosphorylated SEV. role in the of phosphorylated the for the PTP activity of CSW is the we the SH2 domains of CSW with phosphorylated of the SH2 domain for CSW that either of the SH2 domains can at fulfill the SH2 domain for CSW, that SH2 domain capable of binding to phosphorylated We this by the of proteins either or CSW SH2 domains to phosphorylated For these the of phosphorylated an from that and been with the PTP Our results that from such and capable of with CSW R. J.D. T. Simon M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). The results shown in 2 indicate that the SH2 domains of CSW are capable of with mutations of either SH2 domain in a a partial of of SH2 domains binding 2 The of either SH2 domain to function in binding is to in that the SH2 domains are at for CSW function. These are with the that of or the function of the CSW SH2 Our studies that the PTP activity of CSW is for CSW function during photoreceptor (6Allard J.D. Chang H.C. Herbst R. McNeill H. Simon M.A. Development. 1996; 122: 1137-1146Crossref PubMed Google Scholar, R. J.D. T. Simon M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). In we shown that of either of two CSW proteins mutations in the PTP domain and of of the in which are the PTP domain of CSW, these results that CSW PTP activity is important for CSW function during photoreceptor development. these not the activity of CSW required for CSW function. In to that the activity of CSW is for function, these proteins were for their to the of for the csw We also an of CSW in which the entire PTP domain and were of the protein and photoreceptor that were to in either or not We found that of the proteins to the of These results indicate that CSW PTP domain function is for CSW this evidence that CSW PTP activity is for CSW of results with the that CSW function csw a protein that with the function of for these effects is that the proteins their SH2 domains to with CSW for binding to the CSW but then to of the protein has a on photoreceptor than does the of either the or proteins and These results were the csw an conserved that is required for the PTP activity B.G. Tonks N.K. Curr. Opin. Cell Biol. 1997; 9: 193-204Crossref PubMed Scopus (731) Google Scholar, M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). activity not and its have been to the These results that of its signaling its of for these results that the protein at than either the or the We this by that the and the the between the by the two a of in the or of the two CSW proteins, then the of to at as as the The of the were than of and to of These results that the protein of its function and can the of of on the we of the signaling of the Our to a of that function. that CSW function by to the we to the with the at the amino terminus of the The then the of the and the the by The first between the effects of the and either the or that presence of the not a of the of the the of the R7 in approximately of the We then and the The were and in their photoreceptor These results that the of the protein to the to that of CSW and the that of the of CSW can by a catalytically inactive We the of to function by the the of for either the or for the csw is a of to a than such as csw L.A. Johnson M.R. Melnick M.B. Perrimon N. Dev. Biol. 1996; 180: 63-81Crossref PubMed Scopus (100) Google Scholar). to the of the csw In contrast, to the of csw These results that a catalytically inactive CSW protein a of CSW catalytically inactive of CSW can a of function csw of CSW function by the of or csw to in the presence of the as and in a of CSW function by the of or csw to in the presence of the as and between the of CSW and its SHP2 is that CSW contains an insert of approximately 150 amino acids in the of the PTP domain (5Perkins L.A. Larsen I. Perrimon N. Cell. 1992; 70: 225-236Abstract Full Text PDF PubMed Scopus (328) Google Scholar). In to the insert function, an of csw constructed in which this amino acids The CSW protein and assayed for function in of the In the action of from CSW and These results indicate that the PTP insert of CSW is for CSW function. is with the that of which this can for CSW function L.A. Johnson M.R. Melnick M.B. Perrimon N. Dev. Biol. 1996; 180: 63-81Crossref PubMed Scopus (100) Google Scholar). not a role for the insert in CSW function in a manner that is to in these potential function for the of CSW, is as an protein used to to activated RTKs such as the PDGF receptor (9Bennett A.M. Tang T.L. Sugimoto S. Walsh C.T. Neel B.G. Proc. Natl. Acad. S. 1994; PubMed Scopus Google Scholar, R. Cell Biol. 1994; PubMed Google Scholar). The first in this are SHP2 binding to the activated RTK its SH2 SHP2 is then phosphorylated on a tyrosine in in its carboxyl-terminal phosphorylation then as a for the SH2 domain of the of CSW tyrosine phosphorylation in response to SEV activation that this of action does not to SEV signaling, two of evidence have that CSW function in this manner during signaling by other the carboxyl-terminal of CSW includes a tyrosine a to the in (5Perkins L.A. Larsen I. Perrimon N. Cell. 1992; 70: 225-236Abstract Full Text PDF PubMed Scopus (328) Google Scholar). the activated TORSO RTK has been shown to phosphorylated at a that is required for the of CSW with TORSO and the phosphorylation of CSW L.A. Perrimon N. Dev. 1996; 10: PubMed Scopus Google Scholar). In to the role of the carboxyl-terminal of CSW, we a of CSW in which the entire acids The protein the of the the and in of the of CSW function. The activity of to that of CSW in and These results indicate that the of CSW is for CSW function and suggest that the for SHP2 action as an protein phosphorylation of is either not to CSW or is not important for CSW function. These results suggest that the of SHP2 to as an for SHP2 function, as A.M. A.M. Neel B.G. Cell Biol. 1996; PubMed Scopus Google Scholar). In the presence of other mechanisms for and the RTK signaling to function in the of the role of the that CSW does as an phosphorylated at binding sites We have the of of the domains of CSW by CSW proteins with domain-specific mutations and the function of these proteins. Our results indicate that SH2 domain function is required for in function but that this can by either CSW SH2 the of either SH2 domain to CSW function that the binding for the CSW SH2 domain is to binding sites for SH2 for such binding during SEV signaling SEV and DOS, a protein and CSW In this we have shown that although SEV and CSW can from Drosophila their is of CSW SH2 domain function and SEV tyrosine SEV is to a binding for the CSW SH2 We the of CSW and SEV in the R7 cell or is important for SEV In to does binding sites for of the CSW SH2 domains and is a to an important target for the CSW SH2 The of either SH2 domain to CSW function that the two domains have during CSW with biochemical studies of a SH2 domain PTP to CSW and SHP2 that regulates signaling by receptors and RTKs 8: PubMed Scopus Google Scholar, Walsh C.T. Proc. Natl. Acad. S. 1996; PubMed Scopus Google Scholar). These studies that of the SH2 domain of to the activation of PTP deletion of the carboxyl-terminal SH2 domain not PTP These results have to the that the activity of can in two in response to the activation of different such as the receptor, which contain a binding for the SH2 domain of and to the of receptor In contrast, receptors binding sites for the carboxyl-terminal SH2 domain to but not in a of is not such of CSW PTP activity several studies have shown that the binding of SHP2 to can the PTP activity of SHP2 M. I. F. Biol. 1994; Full Text PDF PubMed Google Scholar, M. P. I. R. PubMed Scopus Google Scholar, Sugimoto S. A.M. S.E. Walsh C.T. Neel B.G. Biol. 1993; Full Text PDF PubMed Google Scholar, S. Walsh C.T. S.E. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, S. S.E. Neel B.G. Walsh C.T. Biol. 1994; Full Text PDF PubMed Google Scholar). results suggest that or not such of CSW the binding of CSW to CSW SH2 domain binding the activation of CSW PTP activity by of its SH2 domain is for CSW function to development. Two of evidence suggest that the activity of the PTP domain is also important for CSW function. the of CSW proteins that either contain mutations in the domain or or the entire PTP domain the action of of these proteins is to the of that CSW function. The of to as an that the of is with CSW for SH2 domain binding such as these PTP domain proteins then to the target and to RTK this evidence a role for PTP activity in CSW function, results have that CSW proteins that activity can CSW function. In we have shown that of the protein can the effects of the The of CSW the to function the protein to the with the effects of and also the of that to to the presence of the csw evidence for CSW function with of either of the other PTP domain CSW proteins, the of proteins to is to a of the and studies have that of in which the is to is that such can bind to with For has shown that can a with R. J.D. T. Simon M.A. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). for the of and to function that these proteins can the effects of by binding to the of For example, is in an inactive by an interaction a phosphorylated tyrosine then either by CSW or binding by an inactive CSW the for such a to with that of a in an that binding by the catalytically inactive CSW is than by this a the of the domains of SHP2 during fibroblast growth in has been A.M. Neel B.G. Cell. Biol. PubMed Scopus Google Scholar). SHP2 proteins were assayed for their to the effects on fibroblast growth factor signaling by an SHP2 a deletion the PTP to of CSW function in the presence of the protein and In the of either SH2 domain SHP2/CSW function. the studies were to that SH2 domain mutations SHP2 function, SHP2 carboxyl-terminal SH2 domain function partial function that the protein at Our to the of CSW in the has from CSW proteins carboxyl-terminal SH2 domain function also a of activity in studies were to that the function of of the SH2 domains assayed by the to the of CSW rather than by the to the effects of an We of for the