ライフサイエンスコーパス: Csk

1 Csk and SFKs share a modular design with the kinase doma

2 Csk and Src are two protein tyrosine kinases that share

3 Csk and Src protein tyrosine kinases are structurally ho

4 Csk bound to and phosphorylated PECAM-1 more efficiently

5 Csk cannot phosphorylate substrates that lack this docki

6 Csk catalytic domain is inactive and is positively regul

7 Csk colocalization with G3BP occurred in this "parasynap

8 Csk knock-out mice died at early stages of embryogenesis

9 Csk knockdown induced VE-cadherin phosphorylation at sit

10 Csk migrates to lipid raft domains, where it decreases p

11 Csk plays an important role, not only in basal signaling

12 Csk was translocated to the membrane where it down-regul

13 Csk, in turn, keeps integrin-associated c-Src in an inac

14 ortance of this difference by constructing a Csk variant with a longer SH2 CD loop to mimic the flexi

15 signaling, we generated mice that express a Csk variant sensitive to an analog of the common kinase

16 We have identified a Csk-like kinase (CoCsk) in the genome of C. owczarzaki.

17 tively interacts with its substrate Lck in a Csk-dependent manner.

18 gest that tyrosine-phosphorylated JAM-A is a Csk-binding protein and functions as an endogenous inhib

19 ntaining proteins to the SH2 domain activate Csk.

20 g Csk activity, and their mutation activates Csk, but makes Csk less sensitive to activation by the S

21 the Csk catalytic domain to obtain an active Csk catalytic domain.

22 Although Csk is known as a negative regulator of Src kinases, the

23 Importantly, Src activation and Csk down-regulation are also observed in colon cancer ce

24 However, both c-Src activity and Csk localization at the membrane were similar between Ca

25 c-Src forms a complex with alphaIIbbeta3 and Csk, which phosphorylates c-Src tyrosine 529 to maintain

26 Btk and Csk function downstream of phosphatidylinositol 3-kinase

27 isrupting the association of VE-cadherin and Csk through the reconstitution of Csk binding-defective

28 we show that relative titration of CD45 and Csk expression reveals distinct regulation of basal and

29 uman colon cancer cell lines, HT29 cells and Csk shRNA-transfected HT29 cells that exhibit different

30 Chemical and Csk-based genetic inhibitor treatments revealed that SFK

31 PTPRJ deletion in addition to Chk and Csk ameliorates the extent of thrombocytopenia, suggesti

32 rosine kinases contains two members: Csk and Csk homologous kinase (Chk).

33 he library method to kinases Pim1, MKK6, and Csk revealed that Pim1 and Csk are highly active toward

34 s Pim1, MKK6, and Csk revealed that Pim1 and Csk are highly active toward peptide substrates and reco

35 osis transmembrane conductance regulator and Csk-binding protein were also found to act as transferab

36 re was pronounced colocalization of SFKs and Csk at the site of TCR triggering, whereas in Ag-experie

37 dherin was basally associated with c-Src and Csk (C-terminal Src kinase), a negative regulator of Src

38 For example, in choanoflagellates, Src and Csk are both active, but the negative regulatory mechani

39 Although Src and Csk orthologs are present across holozoan organisms, inc

40 owth assays to characterize holozoan Src and Csk orthologs.

41 ese results, together with available Src and Csk tertiary structures, reveal an important structural

42 Strikingly, Src64 and Csk function in the germline to control packaging, not i

43 ment of Csk to the membrane and that another Csk adaptor, yet to be discovered, compensates for the l

44 reciable differences in domain architecture, Csk from Corallochytrium limacisporum, a highly diverged

45 ssion level of the other membrane-associated Csk adaptor to maintain SFK inhibition.

46 Whereas SFKs are membrane-associated, Csk is a cytoplasmic protein and therefore requires memb

47 F associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds rat

48 Although both Csk and MAP kinases used docking sites for substrate rec

49 First, both Csk and Src phosphorylate Src as a common substrate, but

50 These results uncover novel roles for both Csk and Src64 in a dynamic event that involves adhesion,

51 TRAF3 resulted in increased amounts of both Csk and PTPN22 in T cell membrane fractions and decrease

52 ted to choanoflagellates, Src is active, but Csk is apparently inactive.

53 lation of the N-terminal ITIM of Siglec-9 by Csk is enhanced by the prior phosphorylation of its C-te

54 ation loop (which increases activity) and by Csk-mediated phosphorylation of the C-terminal tail (whi

55 c family tyrosine kinase (SFK) inhibition by Csk.

56 ne 505, which was normally phosphorylated by Csk and dephosphorylated by CD45 in the mutants.

57 In contrast to the role played by Csk in the regulation of Src64 activity during packaging

58 kinases known to be negatively regulated by Csk were then examined; knock down of one of these kinas

59 s suggest that negative regulation of Src by Csk is more ancient than previously thought and that it

60 sphorylation of their C-terminal tyrosine by Csk.

61 high GM3 level by exogenous addition caused Csk translocation into glycosynapse, with subsequent inh

62 kinase), and its transmembrane adaptor, Cbp (Csk-binding protein).

63 es revealed that translocation of Lyn, CD45, Csk, and c-Cbl led to increased recruitment and retentio

64 ial microenvironment: Src-transformed cells (Csk-deficient) were influenced by their immediate normal

65 triggering, whereas in Ag-experienced cells, Csk displayed a bipolar distribution with a proportion o

66 physiological consequences of ablating Chk, Csk, and PTPRJ in mice.

67 hk knockout (KO) mice, reduced by 92% in Chk;Csk double KO (DKO) mice, and partially rescued in Chk;C

68 KO (DKO) mice, and partially rescued in Chk;Csk;Ptprj triple KO (TKO) mice.

69 By contrast, Csk titration regulates basal but not inducible signalin

70 e Csk regulator PAG/Cbp, thereby controlling Csk access to SFKs.

71 on with other Csk orthologs, Corallochytrium Csk displays broad substrate specificity and inhibits Sr

72 during positive selection and to counteract Csk during basal TCR signaling.

73 we utilized a mouse expressing mutated Csk (Csk(AS)) whose catalytic activity is specifically and ra

74 The genetic deletion of Csk (Csk(-)(/)(-)) in mouse embryonic fibroblasts blocked the

75 Thus, recruitment of cytosolic Csk to the membrane-associated SFKs is crucial for its r

76 Reduction in d-Csk expression and the consequent activation of Src are

77 The Drosophila C-terminal Src kinase (d-Csk) is a genetic modifier of warts (wts), a tumor-suppr

78 rity in the loss-of-function phenotypes of d-Csk and wts, we have investigated the interactions of d-

79 , we have investigated the interactions of d-Csk with the Hippo pathway.

80 Previous studies show that d-Csk regulates cell proliferation and tissue size during

81 multiple lines of evidence suggesting that d-Csk regulates growth via the Hippo signaling pathway.

82 SH2 domain whose mutation severely decreases Csk catalytic activity without affecting the SH2 ligand-

83 PTP-1B is required for fibrinogen-dependent Csk dissociation from alphaIIbbeta3, dephosphorylation o

84 Protein (dASPP) as a regulator of Drosophila Csk (dCsk) activity.

85 ow that PSTPIP2 binds the inhibitory enzymes Csk and SHIP1.

86 rodomains (PAG), is the membrane adaptor for Csk.

87 A similar mechanism was confirmed for Csk recognition of another Src family kinase, Yes.

88 First, the SH3-SH2 linker is crucial for Csk activation.

89 a basis for different cellular functions for Csk and Chk.

90 he regulatory domains that are important for Csk activation.

91 ng-based substrate recognition mechanism for Csk.

92 the regulatory region, but not required for Csk activation triggered by a phosphopeptide binding to

93 Our data demonstrate a critical role for Csk in cell migration.

94 and proteins, further supporting a role for Csk in HCV replication.

95 we identified a new Src-independent role for Csk in the control of Gliotactin, a key tricellular junc

96 of six proteins, as follows: BCR, Lyn, Fyn, Csk, PAG1, and Syk, a cytosolic protein tyrosine kinase

97 To investigate how Csk activity regulates T cell antigen receptor (TCR) sig

98 These data identify Csk inhibition as the mechanism through which ibrutinib

99 ase are fast and that a structural change in Csk participates in limiting the catalytic cycle.

100 ic function and interdomain communication in Csk.

101 Interestingly, the preferential decrease in Csk protein synthesis is a consequence of increased eIF2

102 s to recognize substrates is destabilized in Csk by a deletion in the activation loop.

103 largely controlled by one residue, Glu127 in Csk, Ile167 in Chk, and Lys200 in Src.

104 ty of Csk, but were not directly involved in Csk recognition of its physiological substrate, Src.

105 talytic domain, but the equivalent motifs in Csk directly interact with the regulatory domains that a

106 negative regulatory mechanism is present in Csk and Src proteins from C. owczarzaki and the choanofl

107 evated PRL3 expression causes a reduction in Csk level, leading to Src activation.

108 Increased Csk suppresses the Gliotactin overexpression phenotypes

109 ll-atom structure-based simulations indicate Csk occupies two free energy basins.

110 ine and phenylalanine hydroxamates inhibited Csk activity only in the presence of Co(2+).

111 y, and specifically recruited the inhibitory Csk kinase to attenuate TCR signaling, suggesting that T

112 Instead, Csk becomes associated with an approximately 72-kDa tyro

113 here also exists in these cells an intrinsic Csk-dependent cellular defense mechanism aimed at impair

114 C proteins, ezrin binding protein of 50 kDa, Csk binding protein, and the p85 subunit of PI3K was par

115 s thought to be due to the homologous kinase Csk that compensates for Matk/CHK.

116 ibits its association with inhibitory kinase Csk, allowing autophosphorylation of Src at residue tyr4

117 expression of the negative regulatory kinase Csk suppressed SFK activity and reversed the growth-inhi

118 k by opposing the negative regulatory kinase Csk.

119 ch lacks the negative regulatory tail kinase Csk, wild-type Hck was more strongly activated in the pr

120 (LYP), which forms a complex with the kinase Csk and is a critical negative regulator of signaling th

121 ted data and experimental data of the kinase Csk and the adaptor PAG in primary human T cell immunolo

122 To understand how the kinase Csk, a negative regulator of SFKs, controls the basal st

123 Tyrosine kinase Csk is essential for mouse embryonic development.

124 cruits the cytosolic protein tyrosine kinase Csk to the plasma membrane, where it acts to decrease th

125 tyrosine by the nonreceptor tyrosine kinase Csk.

126 report that the nonreceptor-tyrosine-kinase Csk is an essential component of the intracellular modul

127 ylation event include C-terminal Src kinase (Csk) and Bruton's tyrosine kinase (Btk).

128 wn inhibitors of Lck, C-terminal Src kinase (Csk) and protein tyrosine phosphatase N22 (PTPN22).

129 We identified C-terminal Src kinase (Csk) as a tyrosine kinase responsible for regulating Gli

130 presence of the carboxy-terminal Src kinase (Csk) at the cell membrane.

131 cooperative roles of C-terminal Src kinase (Csk) binding protein (Cbp) and Caveolin-1 (Cav-1) in the

132 C-terminal Src kinase (Csk) binds to tyrosine phosphorylated JAM-A through its

133 C-terminal Src kinase (Csk) contains a catalytic domain and a regulatory region

134 The C-terminal Src kinase (Csk) contains a catalytic domain and the regulatory SH3

135 f Src64 by Drosophila C-terminal-Src Kinase (Csk) contributes to the packaging of germline cysts by o

136 The C-terminal Src kinase (Csk) family of protein tyrosine kinases contains two mem

137 C-terminal Src kinase (Csk) is a multidomain tyrosine kinase that is up-regulat

138 The C-terminal Src kinase (Csk) phosphorylates and down-regulates Src family tyrosi

139 C-terminal Src kinase (Csk) phosphorylates and down-regulates the Src family ty

140 C-terminal Src kinase (Csk) specifically phosphorylates Src family kinases on a

141 cells mediated by COOH-terminal Src kinase (Csk) that negatively regulates Pseudomonas invasion.

142 ed inhibitors against C-terminal Src kinase (Csk), a protein tyrosine kinase.

143 tion of Lyn, CD45, COOH-terminal Src kinase (Csk), and c-Cbl were studied by Western blotting, confoc

144 The C-terminal Src kinase (Csk), the primary negative regulator of Src-family kinas

145 SFKs are inhibited by C-terminal Src kinase (Csk), which phosphorylates a conserved tyrosine in their

146 which is catalyzed by C-terminal Src Kinase (Csk).

147 C-terminal region by C-terminal Src kinase (Csk).

148 il by another kinase, C-terminal Src kinase (Csk).

149 ncipal control of the C-terminal Src Kinase (Csk).

150 r negative regulator, C-terminal Src kinase (Csk).

151 The SH2 domain of the C-terminal Src kinase [Csk] contains a unique disulfide bond that is not presen

152 The c-Src tyrosine kinase, Csk, physically interacts with the intracellular phospha

153 Prior studies on protein tyrosine kinases Csk and Src revealed the potential for chemical rescue o

154 rence RNAs specific for three human kinases, Csk, Jak1, and Vrk1, were identified that reproducibly r

155 The kinase activity of full-length Csk decreases by an order of magnitude upon formation of

156 The Csk-binding protein (Cbp) localizes Csk close to its substrates at the plasma membrane, and

157 This suggests that the Lyp-Csk complex increases susceptibility to lupus at multipl

158 ts in the LYP-R620W variation within the LYP-Csk interaction motif.

159 and their mutation activates Csk, but makes Csk less sensitive to activation by the SH2 ligand.

160 dressed the mechanism by which PRL3 mediates Csk down-regulation.

161 otein tyrosine kinases contains two members: Csk and Csk homologous kinase (Chk).

162 with glycosphingolipid-enriched microdomains/Csk binding protein (PAG/Cbp), an adaptor protein that c

163 However, recent structural studies of mutant Csk in the presence of an inhibitor indicate that the en

164 ling, we utilized a mouse expressing mutated Csk (Csk(AS)) whose catalytic activity is specifically a

165 However, dominant negative Csk expression was unable to induce changes in the monol

166 f SFK by overexpression of dominant negative Csk induced VE-cadherin phosphorylation at tyrosines 658

167 and SFKs by expression of dominant negative Csk, expression of constitutively active Src, or knockdo

168 th kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95%

169 G3BP reduced the ability of Csk to phosphorylate Lck at Y505 by decreasing the amoun

170 but proceed constitutively in the absence of Csk.

171 n mediating a ligand-triggered activation of Csk because their mutation severely reduces Csk activati

172 se residues likely mediate SH2 activation of Csk regardless of SH2-ligand interaction.

173 mediating SH2 ligand-triggered activation of Csk.

174 Specifically, we titrated the activities of Csk and CD45 and assessed their influence on Lck activat

175 o demonstrate that the catalytic activity of Csk is required for its modulatory function.

176 crucial in maintaining the full activity of Csk, but were not directly involved in Csk recognition o

177 late Lck at Y505 by decreasing the amount of Csk in lipid rafts.

178 r signaling and acts to reduce the amount of Csk in the immune synapse.

179 tion then confirmed increased association of Csk with phosphomimicking Cav-1.

180 osphorylation of Src and the conformation of Csk were investigated in the presence of a high-affinity

181 nsembles of distinct global conformations of Csk: a compact structure and an extended structure.

182 n the gene-specific translational control of Csk expression.

183 The genetic deletion of Csk (Csk(-)(/)(-)) in mouse embryonic fibroblasts blocke

184 Deletion of Csk and PTPRJ in the MK lineage in mice results in incre

185 Furthermore, deletion of Csk did not interfere with Rac activation and lamellipod

186 activation by blocking the disassociation of Csk from VE-cadherin.

187 n the tyrosine, allowing the dissociation of Csk from the integrin complex, and thus facilitating out

188 ated with Csk, promoting the dissociation of Csk from the plasma membrane.

189 The SH2 domain of Csk is an essential component for the down-regulation of

190 The isolated catalytic domain of Csk is intrinsically inactive and is activated by intera

191 A unique feature of the SH2 domain of Csk is the tight turn in place of the canonical CD loop

192 all Cbp-derived peptide to the SH2 domain of Csk modifies these motions, enhancing Src recognition.

193 e of a complex between the kinase domains of Csk and c-Src at 2.9 A resolution, revealing that intera

194 gest that the Src homology (SH) 2 domains of Csk and Chk may bind to different phosphoproteins, which

195 ween the regulatory and catalytic domains of Csk.

196 ive regulator of Src kinases, the effects of Csk on Gliotactin are independent of Src and likely occu

197 ADP can shift the conformational ensemble of Csk in solution using a combination of small angle x-ray

198 Re-expression of Csk in these Csk-deficient cells rescued the migratory p

199 her share some of the regulatory features of Csk instead.

200 e domain generates further extended forms of Csk that may have relevance for kinase scaffolding and S

201 Thus, the function of Csk as a negative regulator of Src family kinases appear

202 Acute inhibition of Csk revealed that CD45 suppressed zeta-chain phosphoryla

203 Inhibition of Csk(AS) during TCR stimulation led to stronger and more

204 Inhibition of Csk(AS) enhanced activation by weak but strictly cognate

205 Inhibition of Csk(AS) in thymocytes, without engagement of the TCR, in

206 con cells with a small molecule inhibitor of Csk also resulted in a significant reduction in HCV RNA

207 ustering using a small-molecule inhibitor of Csk, which increased SFK activation and produced robust

208 nd evaluated as metal-mediated inhibitors of Csk, leading to improved inhibition and a better underst

209 this study, we generated chimeric kinases of Csk and Src by switching the C-terminal lobes of their c

210 f constitutively active Src, or knockdown of Csk.

211 Loss of Csk causes Gliotactin to spread away from the TCJ.

212 Direct comparison of phenotypes of Csk, Shp1, or CD148 conditional KO mice generated using

213 The Lyn-dependent phosphorylation of Csk-binding protein, which negatively regulates Fyn acti

214 d each SFK with HIV-1 Nef in the presence of Csk.

215 dherin and Csk through the reconstitution of Csk binding-defective mutant of VE-cadherin also diminis

216 at Cbp is dispensable for the recruitment of Csk to the membrane and that another Csk adaptor, yet to

217 Moreover, recruitment of Csk to the specialized membrane compartment of "lipid ra

218 studies demonstrated that the regulation of Csk activity is linked to conformational changes in the

219 protein synthesis, rather than regulation of Csk mRNA levels or protein turnover.

220 ed to be indirect through down-regulation of Csk, a negative regulator of Src.

221 es Src activation through down-regulation of Csk, a negative regulator of Src.

222 play an important role in the regulation of Csk.

223 ell antigen receptor results in a removal of Csk from the lipid raft-associated transmembrane protein

224 Despite the fundamental role of Csk in controlling cell growth and differentiation, it i

225 of PRL3 in tumor metastasis and the role of Csk in controlling Src activity, we addressed the mechan

226 l of c-Src at the edge of the active site of Csk.

227 tant for maintaining the active structure of Csk by the presence of the regulatory region, but not re

228 Although the X-ray structure of Csk suggests the enzyme is compact, X-ray scattering stu

229 This report extended previous studies of Csk domain-domain communication, and provided a foundati

230 Crystallographic studies of Csk found an unusual arrangement of the SH2 and SH3 regu

231 family kinases are the only known targets of Csk.

232 ough its catalytic loop is more like that of Csk.

233 Titration of Csk inhibition revealed that a very small increase in SF

234 des functional insights into the topology of Csk family of protein tyrosine kinases.

235 edback mechanisms, including upregulation of Csk homologous kinase (Chk) expression.

236 PRL3 is shown to exert a negative effect on Csk protein synthesis, rather than regulation of Csk mRN

237 o show that bistability can arise in Lyn- or Csk-deficient cells.

238 However, in comparison with other Csk orthologs, Corallochytrium Csk displays broad substr

239 gulation of Src64 activity during packaging, Csk is dispensable for ring canal growth control, indica

240 The kinase-phosphatase pair Csk and CD45 reciprocally regulate phosphorylation of th

241 cells, in the context of its binding partner Csk, unmasks the risk allele as a hypomorph.

242 bstrate and phosphatase SHP-1 as a potential Csk substrate.

243 n analog of the common kinase inhibitor PP1 (Csk(AS)).

244 family kinase negative regulatory proteins, Csk (C-terminal Src kinase), and its transmembrane adapt

245 PDGF-elicited c-myc induction by recruiting Csk to active Src kinases, whereupon their activities an

246 tively regulate c-Src activity by recruiting Csk to the membrane where it phosphorylates c-Src inhibi

247 Thus, JAM-A recruits Csk to the integrin-c-Src complex in resting platelets.

248 JAM-A recruits Csk to the integrin-c-Src complex, where Csk negatively

249 Reduced Csk synthesis also occurs in response to cellular stress

250 Csk because their mutation severely reduces Csk activation by the SH2 domain ligand.

251 l line (CSK-) lacking the negative regulator Csk gene of the Src kinase family.

252 The roles of Src and its negative regulator Csk have been extensively studied, although results have

253 d, a single point mutation of E127K rendered Csk responsive to activation by a Src SH2 domain ligand.

254 Second, Csk and Src represent two general regulatory strategies

255 The selected Csk substrates show strong sequence covariance and fall

256 A member of this family, SLP65/SLP76, Csk-interacting membrane protein (SCIMP), recruits a com

257 Cardiac-specific Csk knockout in mice led to increased AF, left atrial en

258 TP-1B recruitment to the alphaIIbbeta3-c-Src-Csk complex in a manner that is dependent on c-Src and s

259 to the same degree seen in the mammalian Src/Csk pair.

260 VEGF stimulated Csk release from VE-cadherin by recruiting the protein t

261 Type II residues are involved in suppressing Csk activity, and their mutation activates Csk, but make

262 Our data demonstrate that Csk is involved in the control of cGMP levels and that m

263 We have previously determined that Csk recognizes Src using a substrate-docking site away f

264 e, providing the first in vivo evidence that Csk regulates SFKs during development through phosphoryl

265 Here we report that Csk deficiency in mouse embryonic fibroblast cells block

266 n contrast to previous studies, we show that Csk from the filasterean Capsaspora owczarzaki is active

267 ulation of the HCV replicon, suggesting that Csk mediates its effect on HCV replication through Fyn.

268 It suggests that Csk adopts a broad ensemble of conformations in solution

269 The Csk tyrosine kinase negatively regulates the Src family

270 The Csk-binding protein (Cbp) localizes Csk close to its sub

271 ologic inhibitor of Src kinase activity, the Csk homologous kinase (CHK), expressed as a mammary tiss

272 ween the docking determinants of Src and the Csk substrate-docking site for this recognition.

273 striking functional differences between the Csk and Chk SH2 domains and revealed functional similari

274 ocking determinants in Src recognized by the Csk substrate-docking site and demonstrated an interacti

275 utating Lys200 in Src SH2 domain to Glu (the Csk counterpart) resulted in loss of Src SH2 function.

276 the apparent phosphoryl transfer rate in the Csk active site, a phenomenon detected in rapid quench f

277 Mutating these residues in the Csk or Chk SH2 domain to the Src counterpart resulted in

278 Mechanistically, the Csk-recruiting ITAM of CD3epsilon reduced CAR-T cytokine

279 ion by regulating the phosphorylation of the Csk regulator PAG/Cbp, thereby controlling Csk access to

280 e, we compared the binding properties of the Csk, Chk, and Src SH2 domains and investigated the struc

281 ng chemical and genetic perturbations of the Csk/CD45 regulatory axis incorporated with computational

282 ganisms, including animals and protists, the Csk-Src negative regulatory mechanism appears to have ev

283 tro and transgenic models suggested that the Csk-binding protein (Cbp), also known as phosphoprotein

284 Capsaspora owczarzaki is active and that the Csk-Src negative regulatory mechanism is present in Csk

285 The Src motifs can be grafted to the Csk catalytic domain to obtain an active Csk catalytic d

286 Re-expression of Csk in these Csk-deficient cells rescued the migratory phenotype.

287 ibiting the c-Src activity, possibly through Csk translocation.

288 Thus, Csk has a critical role in preventing TCR signaling.

289 c pathway activity, most likely by titrating Csk activity away from endogenous Src.

290 its Csk to the integrin-c-Src complex, where Csk negatively regulates c-Src activation, thereby suppr

291 ox because of this cysteine residue, whereas Csk, a PTK that lacks a cysteine residue at the correspo

292 TRAF3 associated with Csk, promoting the dissociation of Csk from the plasma m

293 in-1 were phosphorylated and associated with Csk.

294 exhibits a greatly reduced interaction with Csk and is a gain-of-function inhibitor of signaling.

295 ons and decreased association of PTPN22 with Csk.

296 Chk in platelets, functional redundancy with Csk, and the physiological consequences of ablating Chk,

297 Matk/CHK is not functionally redundant with Csk, and that this tyrosine kinase plays an important ro

298 tion of SFKs leads to thrombocytopenia, with Csk being the dominant inhibitor in platelets and Chk ha

299 monstration that replicon cells treated with Csk inhibitor contained lower levels of the phosphorylat

300 We find wt-Csk frequently occupies an extended conformation where t

301 To investigate whether wt-Csk may also access open conformations we applied small