C-terminal Src Kinase-homologous Kinase (CHK), a Unique Inhibitor Inactivating Multiple Active Conformations of Src Family Tyrosine Kinases

The Src family of protein kinases (SFKs) mediates mitogenic signal transduction, and constitutive SFK activation is associated with tumorigenesis. To prevent constitutive SFK activation, the catalytic activity of SFKs in normal mammalian cells is suppressed mainly by two inhibitors called C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK), which inactivate SFKs by phosphorylating a consensus tyrosine near the C terminus of SFKs (YT). The phosphorylated YT intramolecularly binds to the SH2 domain of SFKs. This interaction, known as pYT/SH2 interaction, together with binding between the SH2 kinase linker and the SH3 domain of SFKs (linker/SH3 interaction) stabilizes SFKs in a “closed” inactive conformation. We previously discovered an alternative mechanism CHK employs to inhibit SFKs. This mechanism, referred to as the non-catalytic inhibitory mechanism, involves tight binding of CHK to SFKs; the binding alone is sufficient to inhibit SFKs. Herein, we constructed multiple active conformations of an SFK member, Hck, by systematically disrupting the two inhibitory interactions. We found that CHK employs the non-catalytic mechanism to inactivate these active conformations of Hck. However, CHK does not bind Hck when it adopts the inactive conformation in which both inhibitory interactions are intact. These data indicate that binding of CHK to SFKs via the non-catalytic mechanism is governed by the conformations of SFKs. Although CSK is also an inhibitor of SFKs, it does not inhibit SFKs by a similar non-catalytic mechanism. Thus, the non-catalytic inhibitory mechanism is a unique property of CHK that allows it to down-regulate multiple active conformations of SFKs. The Src family of protein kinases (SFKs) mediates mitogenic signal transduction, and constitutive SFK activation is associated with tumorigenesis. To prevent constitutive SFK activation, the catalytic activity of SFKs in normal mammalian cells is suppressed mainly by two inhibitors called C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK), which inactivate SFKs by phosphorylating a consensus tyrosine near the C terminus of SFKs (YT). The phosphorylated YT intramolecularly binds to the SH2 domain of SFKs. This interaction, known as pYT/SH2 interaction, together with binding between the SH2 kinase linker and the SH3 domain of SFKs (linker/SH3 interaction) stabilizes SFKs in a “closed” inactive conformation. We previously discovered an alternative mechanism CHK employs to inhibit SFKs. This mechanism, referred to as the non-catalytic inhibitory mechanism, involves tight binding of CHK to SFKs; the binding alone is sufficient to inhibit SFKs. Herein, we constructed multiple active conformations of an SFK member, Hck, by systematically disrupting the two inhibitory interactions. We found that CHK employs the non-catalytic mechanism to inactivate these active conformations of Hck. However, CHK does not bind Hck when it adopts the inactive conformation in which both inhibitory interactions are intact. These data indicate that binding of CHK to SFKs via the non-catalytic mechanism is governed by the conformations of SFKs. Although CSK is also an inhibitor of SFKs, it does not inhibit SFKs by a similar non-catalytic mechanism. Thus, the non-catalytic inhibitory mechanism is a unique property of CHK that allows it to down-regulate multiple active conformations of SFKs. C-terminal Src kinase-homologous kinase (CHK), a unique inhibitor inactivating multiple active conformations of Src family tyrosine kinases.Journal of Biological ChemistryVol. 290Issue 1PreviewVOLUME 281 (2006) PAGES 32988–32999 Full-Text PDF Open Access The Src family of protein-tyrosine kinases (SFKs) 4The abbreviations used are: SFK, Src family kinase; CSK, C-terminal Src kinase; CHK, CSK-homologous kinase; Hck, hematopoietic cell kinase; YT, consensus tyrosine near the C terminus of SFKs; HIV-1, human immunodeficiency virus, type 1; SH2, Src homology domain 2; GST, glutathione S-transferase; Ni-NTA, nickel-nitrilotriacetic acid; IP, immunoprecipitation. plays crucial roles in controlling a wide array of cellular functions, including growth, proliferation, and differentiation (1Thomas S.M. Brugge J.S. Annu. Rev. Cell Dev. Biol. 1997; 13: 513-609Crossref PubMed Scopus (2164) Google Scholar, 2Bjorge J.D. Jakymiw A. Fujita D.J. Oncogene. 2000; 19: 5620-5635Crossref PubMed Scopus (338) Google Scholar). Aberrant regulation of the SFK activity is associated with malignant transformation of healthy cells (see Refs. 3Irby R.B. Yeatman T.J. Oncogene. 2000; 19: 5636-5642Crossref PubMed Scopus (690) Google Scholar and 4Frame M.C. Biochim. Biophys. Acta. 2002; 1602: 114-130Crossref PubMed Scopus (0) Google Scholar, for review). In light of the oncogenic potential of SFKs, it is vital that their basal activity is kept low. The major inhibitory mechanism that suppresses SFK activity is contingent upon phosphorylation of a consensus tyrosine in the C-terminal tail of SFKs (YT). Upon YT phosphorylation, SFKs tend to adopt a “closed” inactive conformation in which the catalytically critical residues are not properly aligned for productive substrate phosphorylation. Although YT phosphorylation is generally associated with SFK inhibition, there exist several active conformations of SFKs in which their YT is phosphorylated (5Chong Y.P. Ia K.K. Mulhern T.D. Cheng H.C. Biochim. Biophys. Acta. 2005; 1754: 210-220Crossref PubMed Scopus (88) Google Scholar). In this article, we demonstrate that the CSK-homologous kinase (CHK) is a unique inhibitor capable of inhibiting these and other active conformations of SFKs regardless of their YT phosphorylation status. C-terminal Src kinase (CSK) and CHK are two principal endogenous negative regulators of SFKs that inactivate SFKs by phosphorylating their YT (see Refs. 5Chong Y.P. Ia K.K. Mulhern T.D. Cheng H.C. Biochim. Biophys. Acta. 2005; 1754: 210-220Crossref PubMed Scopus (88) Google Scholar and 6Cheng H.C. Chong Y.P. Ia K.K. Tan O. Mulhern T.D. AfCS-Nature Molecule Pages. 2006; 10.1038/mp.a000705.01Google Scholar for review). As revealed by crystal structures of the YT-phosphorylated forms of two SFK members c-Src and Hck, the inactive SFKs adopt a closed conformation stabilized by two major intramolecular inhibitory interactions (7Xu W. Harrison S.C. Eck M.J. Nature. 1997; 385: 595-602Crossref PubMed Scopus (1249) Google Scholar, 8Sicheri F. Moarefi I. Kuriyan J. Nature. 1997; 385: 602-609Crossref PubMed Scopus (1045) Google Scholar): (i) binding of the phosphorylated YT to the SH2 domain (referred to as the pYT/SH2 interaction), and (ii) binding of a polyproline type II helical motif in the SH2-kinase linker to the SH3 domain (referred to as the linker/SH3 interaction). In mammalian cells, activation of SFKs is accomplished by multiple mechanisms that disrupt one or both inhibitory interactions (see Refs. 9Miller W.T. Acc. Chem. Res. 2003; 36: 393-400Crossref PubMed Scopus (60) Google Scholar and 10Lerner E.C. Trible R.P. Schiavone A.P. Hochrein J.M. Engen J.R. Smithgall T.E. J. Biol. Chem. 2005; 280: 40832-40837Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar for review). For instance, Hck is activated by the accessory protein Nef of human immunodeficiency virus-1 (HIV-1), which binds to the SH3 domain, and in turn disrupts the linker/SH3 interaction of Hck (11Saksela K. Cheng J. PubMed Scopus Google Scholar). is that of the linker/SH3 interaction alone is sufficient to Hck activation, the pYT/SH2 interaction E.C. Smithgall T.E. Biol. 2002; Google Scholar, Kuriyan J. W.T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). of capable of SFKs by the linker/SH3 interaction in are W.T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and the S.M. W.T. Full Text Full Text PDF PubMed Scopus Google Scholar). In of the pYT/SH2 interaction alone also SFKs E.C. Smithgall T.E. Biol. 2002; Google Scholar). The the is a SH2 to Hck by the of the SH2 domain Kuriyan J. W.T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, F. R.B. Full Text PDF PubMed Scopus Google Scholar, I. F. Kuriyan J. W.T. Nature. 1997; 385: PubMed Scopus Google Scholar). kinase and a protein are with functions, c-Src by disrupting the linker/SH3 and pYT/SH2 interactions J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. Dev. PubMed Scopus Google Scholar). of YT to a for SFKs to adopt the closed inactive conformation. However, there exist multiple endogenous that SFKs by the linker/SH3 pYT/SH2 interactions the YT phosphorylation status. This that phosphorylation of YT alone is to SFK activity the basal (see 5Chong Y.P. Ia K.K. Mulhern T.D. Cheng H.C. Biochim. Biophys. Acta. 2005; 1754: 210-220Crossref PubMed Scopus (88) Google Scholar for review). Thus, in to phosphorylation of YT by CSK and CHK, inhibitors capable of SFK activity by mechanisms are (see 5Chong Y.P. Ia K.K. Mulhern T.D. Cheng H.C. Biochim. Biophys. Acta. 2005; 1754: 210-220Crossref PubMed Scopus (88) Google Scholar for review). we that CHK inactivate SFKs in and in cells by a non-catalytic mechanism that does not YT phosphorylation. this mechanism is binding of CHK to SFKs to protein Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The binding is of YT phosphorylation by CHK and is referred to as non-catalytic This non-catalytic binding alone is sufficient to the activity and of SFKs. To the of we in that in cells, (i) CHK and c-Src in and (ii) CHK and c-Src a protein These two of the that of CHK and c-Src their in and in turn their binding to the CHK binding suppresses the activity of c-Src in the are two (i) CHK this non-catalytic mechanism to inhibit active conformations of (ii) CHK bind to the inactive conformation of In this we the SFK Hck as a and constructed multiple active conformations of Hck by systematically disrupting the linker/SH3 and pYT/SH2 inhibitory interactions. We that CHK binds to and these active conformations of Hck. However, it does not bind to Hck in the inactive conformation of which both inhibitory interactions are intact. These data that the conformation of SFKs plays a crucial in the non-catalytic binding and CSK is endogenous inhibitor of SFKs (see Mulhern T.D. Cheng 2005; PubMed Scopus Google Scholar for we also it the to inactivate SFKs by a similar non-catalytic mechanism. data indicate that CSK is of inhibiting SFKs by a mechanism. we that the non-catalytic inhibitory mechanism is a unique of CHK it to inhibit multiple active conformations of SFKs. type CHK in cells as previously Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). CSK S.M. Biol. 13: PubMed Scopus Google and CSK by K. J. PubMed Scopus Google Scholar). of the SFK C-terminal and of to previously J.D. Fujita D.J. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. Fujita D.J. Cheng H.C. J. Res. 1997; PubMed Scopus Google Scholar). of the and Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. Fujita D.J. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The the consensus of SFKs (referred to as the and the consensus C-terminal tyrosine of SFK members (referred to as the and Cell The Cell by Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). with to it as previously with the Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). as previously E.C. Smithgall T.E. Biol. 2002; Google Scholar). a protein of the of in The by used to in by the by the of the in which both linker are with and the C-terminal tail is to the SH2 binding E.C. Smithgall T.E. Biol. 2002; Google Scholar). the human Hck This the for in mammalian The the of of of SFK by of residues is upon the of the of Hck the Hck The in a as previously A. Cheng H.C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The to the to the of the in these by The with the cells to the and of the and and in the of cells by and The by by in the by the protein kinase activity as as in the by and of YT-phosphorylated Hck and and and by cells with the of Hck or and consensus and the C-terminal phosphorylation are referred to as and For the these residues to and The allows phosphorylation of YT of Hck and by is that not Hck phosphorylated by Thus, in to the of Hck the also other forms of Hck including Hck and of type Hck and Hck the Hck of and two forms of Hck and by and as previously A. Cheng H.C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the to a the which Hck and not and the to a of of with and The or and by and and to phosphorylation of these of YT-phosphorylated by phosphorylating with CSK in and CSK in the of and for the by as in the The by and of the of domain by residues of CHK by by the of the domain T.D. To Cheng H.C. J. 2002; PubMed Scopus Google Scholar). For the of the CHK kinase domain, residues of CHK by The the The kinase domain used to the of CHK kinase and of and and CHK in of the and of CHK as previously T.D. To Cheng H.C. J. 2002; PubMed Scopus Google Scholar). For the CHK kinase domain, by the CHK kinase domain in cells as previously Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the protein by and The protein by by CHK kinase domain in the by and kinase activity as previously Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). SH2 of the SH2 domain of SFKs. The of and of used in the to binding of the to and not protein with of to of the in a of in for The for and the the and by The with of of in and of in to the by and with SFKs in conformations for To the the to with of For the IP, the to the to by of the for the the with in to in the by and by To the of disrupting the pYT/SH2 interaction CHK and with for to The similar of between CHK and in cells with or or with both The as previously Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the cell of with to of to of for with The as previously Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to CHK and by Hck and to with the of CHK or CSK for and and to the These for to of the by Hck and active the is phosphorylated by Hck it is a substrate of CHK Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and CSK not To the phosphorylation of by CSK or CHK, with CSK or CHK as previously J.R. PubMed Scopus Google Scholar). To the of CHK to inhibit the Hck activated with for the The catalytic activity of the Hck in the of CHK by kinase for the in of the cells with the (i) (ii) and and as previously Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). activity in the of by the kinase as Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The Src which is a and substrate for Hck, used as substrate of this The phosphorylation for and the phosphorylated by the J.D. Fujita D.J. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of in the SFK by SFKs as and of protein by and The SFKs with of in for a with a a of to C with in a of and for by an with a of the of SFKs and the conformations of Hck and and their used in this the of these The of the SH2 kinase linker kinase domain and C-terminal domain and in that YT are the and in the SH2 kinase linker capable of a type II helical that with the SH3 domain, are to This is active E.C. Smithgall T.E. Biol. 2002; Google and is to of the of the SH2 kinase linker to in the linker/SH3 interaction of of the in the by and not This also an C-terminal tail the type to The motif of the C-terminal tail is an substrate of SFKs J.D. Fujita D.J. Cheng H.C. J. Res. 1997; PubMed Scopus Google Scholar). is that the motif in cells E.C. Smithgall T.E. Biol. 2002; Google Scholar, Kuriyan J. W.T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). We the phosphorylation of of the the phosphorylated C-terminal tail of and Hck in to the phosphorylated C-terminal tail of type and Hck, this also with in the C-terminal tail of The of this in the C-terminal tail by data in of the with it The of to to which to the SH2 that YT of this is phosphorylated and in intramolecular pYT/SH2 interaction is in a For the with type Hck, and phosphorylated by CSK, that are phosphorylated YT not YT phosphorylation in the For the and their of phosphorylation and YT by CHK and the SH3 and SH2 crystal of inactive Hck that the linker/SH3 and pYT/SH2 interactions are to SFKs in a closed inactive conformation. In this we of both intramolecular inhibitory interactions the of CHK to inhibit SFKs. is a Hck that the SH3 and SH2 and is to the inhibitory interactions. As in CHK the catalytic activity and suppresses of this that CHK binds to this to a protein and the in the of that the SH3 and SH2 and is not to by YT phosphorylation, CHK the mechanism to inhibit this this mechanism allows CHK to inhibit SFKs by binding to we previously referred it as the non-catalytic inhibitory mechanism Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Although of is by non-catalytic binding with CHK, we the binding involves residues YT near the C terminus of Hck. For this we the of a the of SFK C-terminal the binding and We that this not the of CHK to bind and inhibit C and These data that the interaction is not by the YT of SFKs. In the data indicate that a motif in the residues of Hck. CHK the of Hck by of the activation in is associated with Thus, it a that of is a for SFK However, there are to this we and that accessory protein Nef binds to the SH3 domain of Hck and in turn the linker/SH3 interactions E.C. Smithgall T.E. Biol. 2002; Google Scholar, I. F. Kuriyan J. W.T. Nature. 1997; 385: PubMed Scopus Google Scholar, K. Kuriyan J. Full Text Full Text PDF PubMed Scopus Google Scholar). This is sufficient to Hck E.C. Smithgall T.E. Biol. 2002; Google Scholar, I. F. Kuriyan J. W.T. Nature. 1997; 385: PubMed Scopus Google Scholar). these we the that the conformation of Hck, the linker/SH3 interaction of this is by of the in the motif with However, the pYT/SH2 interaction is by the C-terminal with the As the is an SFK phosphorylation this the C-terminal tail E.C. Smithgall T.E. Biol. 2002; Google Scholar). The by J.M. PubMed Scopus Google that of the domain the motif is that the C-terminal tail of an SFK a property is to the pYT/SH2 interaction in this not bind to the that SH2 domain is in the intramolecular pYT/SH2 kinase activity and is by CHK of is phosphorylated and to the SH2 domain, CHK the non-catalytic mechanism to inhibit this This is by that CHK forms a with this CHK in CHK is capable of inhibiting the active conformation of Hck by of the linker/SH3 interaction in cells, we in cells and the between CHK and this active Hck As in of in cells a in tyrosine phosphorylation of cellular CHK a in the tyrosine phosphorylation of a of CHK the of to tyrosine phosphorylation of the cellular that CHK inhibit the activity of this Hck in In with this that the kinase activity of by of CHK also suppressed in the kinase domain as as the in the unique domain A. Cheng H.C. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). We previously that the C-terminal motif of phosphorylation in mammalian cells E.C. Smithgall T.E. Biol. 2002; Google Scholar). upon phosphorylation, the motif tight pYT/SH2 intramolecular these we that CHK down-regulate by the non-catalytic inhibitory mechanism. This is by the in which between CHK and in the it is and that CHK employs the non-catalytic inhibitory mechanism to down-regulate the active conformation of Hck by of the linker/SH3 interaction in and in to CHK, of the pYT/SH2 the CHK inhibit SFKs activated by disrupting the pYT/SH2 To this we the closed inactive conformation and activated it by SH2 domain the The of CHK to bind and inhibit this activated Kuriyan J. W.T. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google that activation of by the with We used to in As in of this a basal activity of of Upon with the the basal activity by to that activated upon of the intramolecular pYT/SH2 CHK in inhibit both basal and the Hck We the of CHK to bind with and of the pYT/SH2 As in in the of the a of Hck with The to these Hck and that the of Hck to CHK is or that Hck is not phosphorylated However, upon activation with the of Hck to CHK by to the in These Hck to CHK phosphorylated YT and that CHK bind and inhibit the via the non-catalytic inhibitory mechanism. the in we also CHK is to bind when it adopts the closed inactive conformation. To this we to an that and and forms of Hck. To this we CSK with the in the of to phosphorylation YT by CSK to a that of type Hck not a of and we in an with to the SH2 domain and As in CHK does not bind and However, when the closed conformation of by the CHK to a protein with and both Hck and the pYT/SH2 interaction, are to adopt similar the crystal of c-Src that the linker/SH3 interaction of the in the of the pYT/SH2 is to that Hck and the also exist in a similar to that of that forms a protein with CHK, that CHK binds and Hck and with linker/SH3 interaction pYT/SH2 In CHK does not bind that Hck the closed inactive conformation is not the of CHK The the is data in that CHK bind and in the closed inactive conformation. To this also to other SFKs, we CHK bind with data in does not a protein with CHK, does the in and that the non-catalytic binding is governed by in SFKs, CHK binds to the not the inactive conformation of SFKs. CSK the to Hck via the of the between CSK and CHK, we in CSK also the to inactivate SFKs by the non-catalytic mechanism. As in CSK to inhibit and CHK suppresses the catalytic activity of both between CSK and the not the that CSK does not the non-catalytic mechanism to inhibit SFKs. data that CSK and CHK are CHK the to down-regulate SFKs by the non-catalytic inhibitory mechanism. CHK with to also to the of CHK for binding to We the of CHK, domain domain and kinase domain We the of these CHK to bind and inhibit The demonstrate that the kinase domain, and not the SH3 and SH2 of CHK, with the does not inhibit the catalytic activity of Hck is data that of and by CHK is by the non-catalytic mechanism of the protein the SH3 domain of CHK does not bind to we that it not Hck As the domain does not the activity of both Hck the that binding is for SFK CHK of adopt multiple active the pYT/SH2 interaction and regulation by these active conformations of SFK are an In this article, we that CHK employs a non-catalytic inhibitory mechanism to the active conformations of SFKs of one or both of the intramolecular inhibitory interactions. However, SFKs adopt the closed inactive CHK is to bind to the of between CSK and CHK, CSK the to inhibit SFKs via a similar non-catalytic mechanism. the that CHK is a unique inhibitor capable of active SFKs two (i) YT phosphorylation and (ii) the non-catalytic inhibitory mechanism. To the of the CHK non-catalytic inhibitory mechanism, we previously that in cells, CHK and c-Src exist in the of the Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of CHK and c-Src the of both and in turn CHK of We also in that CHK, not CSK, forms protein with c-Src in cells Y.P. Mulhern T.D. Fujita D.J. J.D. Cheng H.C. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The that CHK is capable of the non-catalytic mechanism to bind and down-regulate SFKs in The of SFKs to adopt multiple active conformations allows to to Biol. 2002; PubMed Scopus Google Scholar). These (i) that bind to the SH2 and SH3 of SFKs, and (ii) protein that of SFKs. active conformations are when the activated SFKs These active conformations of SFKs the of The active SFKs two of (i) phosphorylation of protein and in turn of their and (ii) binding to cellular via their SH2 and SH3 for the type of is of the kinase activity by c-Src phosphorylation M.C. Res. 2005; PubMed Scopus Google Scholar). The type of the of the SH2 and SH3 For c-Src binds to the via SH3 The binding alone is sufficient to activity J. 2002; PubMed Google Scholar). that CHK multiple active conformations of SFKs, it is that CHK both of by active SFKs. of of SFKs by SFKs adopt the inactive conformation stabilized by the linker/SH3 and pYT/SH2 CHK to bind to and This that binding of CHK to SFKs is a CHK binds to SFKs when are in the active adopt the closed inactive conformation. upon we the mechanism to the of of SFKs by CHK binds to the active conformations of SFKs. of active SFKs is by protein-tyrosine as tyrosine and protein-tyrosine A. J. PubMed Scopus Google Scholar, 2005; PubMed Scopus Google to the SH2 and SH3 SFKs. CHK in the YT of CHK the it adopts the inactive conformation of this (i) of CHK with tyrosine and protein-tyrosine to down-regulate SFKs, and (ii) of of the upon YT phosphorylation by As in E.C. Smithgall T.E. Biol. 2002; Google the conformation of the conformation of Hck activated by Nef binding to SH3 The in and that CHK is capable of inhibiting CHK the non-catalytic mechanism to inhibit Hck is a of In it is also to in CHK binding of the between CSK and CHK in of SFKs in is that CSK SFKs by phosphorylating their YT catalytic CHK both catalytic and non-catalytic inhibitory mechanisms to SFK we that CHK is CSK for SFK in regulation of SFKs by CHK and CSK is governed by including (i) the of CSK, CHK, and SFKs, (ii) catalytic of CSK and CHK in phosphorylating YT of SFKs, and interaction of SFKs with as Nef and J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, R.P. Smithgall T.E. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). of these in cell and in and hematopoietic cells CSK and CHK are both to down-regulate SFKs. For cells CSK other endogenous non-catalytic SFK inhibitors as and with CSK to down-regulate SFK activity (5Chong Y.P. Ia K.K. Mulhern T.D. Cheng H.C. Biochim. Biophys. Acta. 2005; 1754: 210-220Crossref PubMed Scopus (88) Google Scholar, J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Biol. PubMed Google Scholar, 2003; PubMed Scopus Google Scholar). of SFK by the CHK of SFK activation of SFKs is a major of CHK the non-catalytic mechanism to multiple active conformations of SFKs, these non-catalytic inhibitory are potential that the motif tight binding of CHK to SFKs in the CHK kinase domain, the for of SFKs in other of in to the binding and of SFKs by the non-catalytic mechanism of CHK of these We and for their in with

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