ライフサイエンスコーパス: talin

1 vage of paxillin, focal adhesion kinase, and talin).

2 mine relevant functions of the three ABDs of talin.

3 absent in canonical FERM proteins, including talin.

4 3 in a CHO cell system when coexpressed with talin.

5 pid kinase activity and binding affinity for Talin.

6 F3 region, a critically regulated domain in talin.

7 interacts with the major adhesion component, talin.

8 ndependent pathways to undergo activation by talin.

9 r adhesion-related adaptor proteins, such as talin.

10 on through the essential cytoskeletal linker talin.

11 Integrin and the Integrin-associated protein Talin.

12 ral focal adhesion proteins: vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), as well as phos

13 ular phenotypes reported in animal models of talin 1 disruption, implicate impaired structural integr

14 sues, robust immunohistochemical staining of talin 1 was demonstrated in coronary arteries.

15 TLN1 encodes talin 1-a large cytoplasmic protein of the integrin adhe

16 caspase 12 and podocyte cytoskeletal protein talin 1.

17 Moreover, talin-1 and kindlin-3 proteins promote uptake, but not b

18 gulating actin polymerization and binding of talin-1 and kindlin-3 to the beta2 integrin cytoplasmic

19 e platelet-signaling pathways that result in talin-1 binding to the integrin beta cytoplasmic domain

20 , which block Rap1 binding without affecting talin-1 expression, in either the talin-1 F1 domain (R11

21 fied a low-affinity Rap1-binding site in the talin-1 F0 domain that makes a small contribution to int

22 affecting talin-1 expression, in either the talin-1 F1 domain (R118E) alone, which were viable, or i

23 ified an additional Rap1-binding site in the talin-1 F1 domain that makes a greater contribution than

24 Loss of the Rap1-talin-1 F1 interaction in platelets markedly decreases t

25 he nature of the connection between Rap1 and talin-1 in integrin activation is an important remaining

26 d stoichiometric quantities of kindlin-3 and talin-1 in platelets and neutrophils, indicating that re

27 sure of phosphatidylserine, loss of the Rap1-talin-1 interaction in talin-1(R35E, R118E) platelets ha

28 These findings show that talin-1 is the principal direct effector of Rap1 GTPases

29 hate-interacting adaptor molecule (RIAM) for talin-1 recruitment and thus integrin activation, but di

30 g the existence of alternative mechanisms of talin-1 recruitment.

31 by a mechanism involving the recruitment of talin-1 to the cytoplasmic integrin tail.

32 egation in mice whose platelets express only talin-1(R35E, R118E) are even more impaired, resembling

33 ine, loss of the Rap1-talin-1 interaction in talin-1(R35E, R118E) platelets had little effect on thes

34 thermore, we demonstrated that expression of Talin-1, an adaptor protein that regulates LFA-1 affinit

35 interaction in platelets markedly decreases talin-1-mediated activation of platelet beta1- and beta3

36 s progressively impairs the cooperation with talin-1.

37 signaling, which is induced by kindlin-3 and talin-1.

38 d stoichiometric quantities of kindlin-3 and talin-1.

39 ding and refolding of talin rod domains make talin a very effective force buffer that sets a physiolo

40 Talin, a cytoskeletal protein essential in mediating int

41 Talin, a force-bearing cytoplasmic adapter essential for

42 Direct methylation of talin, a key regulatory molecule in cell migration, by E

43 The turnover of the IAC component Talin, a known mechanosensor, was analyzed using fluores

44 A key modulator of integrin activation is talin, a large cytoskeletal protein that exists in an au

45 Whether talin ABDs regulate actin polymerization in a constituti

46 ular structure, and implicating the integrin-talin-actin complex as the primary mechanical linkage in

47 function studies in mice have shown that the talin-activating role of RIAM is neither required for de

48 roles in healthy cells, the dysregulation of talin activators can lead to disease states in which abe

49 site and integrins differs, suggesting that talin adopts different orientations relative to integrin

50 mplexes by pulling VBS peptides derived from talin, alpha-actinin, and Shigella IpaA out of the vincu

51 Talin also links integrins to actin and other proteins t

52 ins with cytoplasmic proteins, in particular talin and actin, and cytoskeletal contraction on them ca

53 ng adaptor molecule (RIAM) or lamellipodin), talin and activated integrins in living cells.

54 ur results showed that the interplay between talin and alpha-actinin regulates signal transmission vi

55 Vinculin has binding sites for talin and F-actin, but effective binding requires vincul

56 In addition, blocking calpain cleavage of talin and FAK in vivo promotes Rohon-Beard peripheral ax

57 Blocking calpain cleavage of talin and FAK inhibits repulsive turning from focal unca

58 -based adhesion assembly through cleavage of talin and FAK, and adhesion disassembly through cleavage

59 hesion dynamics through specific cleavage of talin and FAK.SIGNIFICANCE STATEMENT The proper formatio

60 Here, we identify the adhesion proteins talin and focal adhesion kinase (FAK) as proteolytic tar

61 calpain proteolysis of the adhesion proteins talin and focal adhesion kinase.

62 gulator and altering the interaction between talin and integrin.

63 members of the integrin machinery (including talin and integrins) existed before kindlin emergence in

64 inding of the intracellular adapter proteins talin and its cofactor, kindlin, to the integrin recepto

65 Talin and kindlin are cytoplasmic proteins that bind to

66 How talin and kindlin contribute to these events in non-hema

67 Our findings show that talin and kindlin cooperatively activate integrins leadi

68 mational state and that this requires intact talin and kindlin motifs.

69 e, we demonstrate that the interplay between talin and kindlin promotes integrin activation.

70 which determines the association with either talin and kindlin-2, the major integrin activators, or f

71 M is recruited to immune synapses along with talin and LFA-1, and loss of RIAM profoundly suppresses

72 Interestingly, C3G bound to talin and promoted the interaction of talin with beta1A-

73 Perturbation of talin and Syk demonstrated that a talin-dependent link b

74 bi-molecular complex with the head domain of talin and thereby promotes beta3 integrin activation.

75 bound to domains of the cytosolic regulator talin and to extracellular ligands.

76 Two key proteins talin and vinculin connecting integrin to actomyosin net

77 e demonstrate how the actin-binding proteins talin and vinculin cooperate to provide this link.

78 lar traction force generation, which affects talin and vinculin dynamics in cell-matrix adhesions and

79 Instead, we found paxillin together with talin and vinculin in initial adhesion patches of kindli

80 d to a model whereby paxillin contributes to talin and vinculin recruitment into nascent adhesions.

81 We also found that paxillin can bind to both talin and vinculin when either is inactive.

82 re enriched in the adhesion-related proteins talin and vinculin, have a central core of tyrosine phos

83 ulin and, to a lesser extent, alpha-actinin, talin, and filamin, to phosphomimetic Cav1Y14D relative

84 nositide-rich membranes recruit and activate talin, and the membrane-bound talin then activates vincu

85 nase signalling to build a mechanosensitive, talin- and vinculin-mediated, focal adhesion-like molecu

86 As expected, full-length vinculin and talin are autoinhibited and do not interact with each ot

87 udied focal adhesions: 1) integrin beta5 and talin are present at high density, at the edges of corne

88 sition kinetics of the 13 helical bundles of talin are utilized in the diverse talin-dependent mechan

89 Talins are adaptor proteins that regulate focal adhesion

90 Thus, talins are essential for kidney collecting duct developm

91 Our results identify talin as the primary determinant of FA nanoscale organiz

92 ) and together with the cytoskeletal protein talin assemble into a signaling complex upon E-cadherin

93 ermore, we showed that alpha-actinin promote talin association with beta1-integrin by restricting the

94 Mice with defective talin autoinhibition exhibit delays in melanoblast migra

95 essential for melanoblast migration and that talin autoinhibition is an important mechanism for fine-

96 shows that C3G binds to the interface of the talin-beta-integrin complex, acting as an allosteric reg

97 HUTS-21 anti-beta1antibody and by increased talin-beta1 association.

98 l inhibitors, we define here a MAP4K4-moesin-talin-beta1-integrin molecular pathway that promotes eff

99 Although talin binding is sufficient for inside-out activation of

100 We have defined the role of talin binding to the beta1 proximal NPxY motif in the de

101 pairs integrin signaling by both undermining talin binding to the beta3-integrin cytoplasmic tail and

102 How intracellular signals promote talin binding to the integrin tail leading to integrin a

103 tutive integrin phosphorylation, exaggerated talin binding, increased integrin activity, and enhanced

104 c tail and reducing the entropic barrier for talin binding.

105 n by itself to localize the membrane and the talin-binding site.

106 grin activation and adhesion, Mn(2+) enabled talin- but not kindlin-deficient cells to initiate sprea

107 at reduction in the integrin-binding protein Talin can partially rescue glial compression.

108 est a model whereby force acting on integrin-talin complexes via ABS3 promotes R3 unfolding and vincu

109 Experiments with truncated forms of talin confirm the mechanosensory role of the talin R3 su

110 Talin contains three actin-binding domains (ABDs).

111 that vinculin, through its interaction with talin, controls milk protein gene expression.

112 n of the integrin-associated adapter protein talin coordinates cell-ECM adhesion during melanoblast m

113 Talin critically controls integrin-dependent cell migrat

114 Restoring beta1-integrin activation in talin-deficient cells with a beta1-integrin activating a

115 Talin-deficient endothelium showed altered VE-cadherin o

116 Peripheral talin-deficient Treg cells were unable to maintain high

117 Talin-dependent activation of EC beta1-integrin stabiliz

118 rbation of talin and Syk demonstrated that a talin-dependent link between integrin and actin and Syk-

119 bundles of talin are utilized in the diverse talin-dependent mechanosensing processes remains poorly

120 on of either the talin head or rod domain in talin-depleted cells restores early adhesion formation.

121 e rate of cell migration and also found that talin destabilization affects the usage of different int

122 Talin diagonally spans the FA core, with its N terminus

123 Talins directly bind integrins and are essential for int

124 p sizes and the folding properties of the R3 talin domain.

125 We show that distinct combinations of talin domains are required for each of three different i

126 tegrin complexes containing kindlin, but not talin, emerge.

127 Here we show structurally that talin-F0 binds to human Rap1b like canonical Rap1 effect

128 mammalian small GTPase Rap1 is known to bind talin-F0 domain but the binding was shown to be weak and

129 Our experiments demonstrate that talin filters out external mechanical noise but detects

130 f the FA and invadopodia-associated proteins talin, focal adhesion kinase (FAK), and cortactin and re

131 ining paxillin and vinculin can form without talin following integrin activation.

132 f beta3-integrin, whereas it cooperates with talin for activating integrin alpha5beta1.

133 4K4 to inactivate integrin by competing with talin for binding to beta1-integrin intracellular domain

134 been shown that alpha-actinin competes with talin for binding to the cytoplasmic tail of beta3-integ

135 lin, vinculin, and p130Cas, and they require talin for their formation.

136 nd depend on these integrins and the adaptor Talin for their retention in blood-exposed regions of th

137 A new study reveals that a protein called talin forms a vital link between microtubules and focal

138 Overall, these results shed new light on talin function and constrain models for cellular mechano

139 e findings demonstrate that the mechanism of talin function differs in each developmental context exa

140 in, which disrupts KANK1 binding but not the talin function in adhesion, abrogates the association of

141 best explained by alternative mechanisms of talin function, with talin using one or both of its inte

142 There are two talin genes, Tln1 and Tln2, which encode talin1 and tali

143 There are two talin genes, Tln1 and Tln2.

144 Talin has attracted great interest in the field of mecha

145 reexpression of talin or integrin activating talin head domain but not a talin head domain mutant tha

146 The talin head domain consists of four distinct lobes design

147 egrin activating talin head domain but not a talin head domain mutant that is selectively deficient i

148 grin alphaIIbbeta3, co-expression of K2 with talin head domain resulted in robust integrin activation

149 ctivation involves the direct binding of the talin head domain to the switch region 2 sequence of the

150 coding the N-terminal fragment of talin (the talin head domain) with a subsequent insertion of the PH

151 n-related protein) domain, also known as the talin head domain, and a series of helical bundles known

152 present a crystal structure of a full-length talin head in complex with the beta3-integrin tail.

153 adhesions form, but expression of either the talin head or rod domain in talin-depleted cells restore

154 l characterization of the FERM-folded active talin head provides fundamental understanding of the reg

155 interaction is released, the integrin-bound talin head retains the ability to inhibit actin assembly

156 rupting the FERM-folded configuration of the talin head significantly impairs integrin activation and

157 Although the talin head, the integrin-binding segment in talin, posse

158 bserved effects are caused by the release of talin head-rod autoinhibition.

159 Vertebrates have two highly conserved talin homologs that differ in their expression patterns.

160 EC-specific deletion of talin in adult mice resulted in impaired stability of in

161 New data have implicated a role for talin in diseases that are highly regulated by mechanica

162 We find that talin in focal adhesions is under tension, which is high

163 The requirement for talin in maintaining high IL-2Ralpha expression by Treg

164 In this study, we describe a role for talin in maintaining the homeostasis and survival of the

165 unactivated platelets, but becomes bound to talin in response to elevated intraplatelet calcium leve

166 While force on talin in small lamellipodial adhesions correlated with a

167 nction of Ena/VASP, alpha5beta1-integrins or talin in the somitic cells abolished the FN pillars, ind

168 T cell-specific deletion of talin in Tln1(fl/fl)Cd4(Cre) mice resulted in spontaneou

169 tively, our data suggest a critical role for talin in Treg cell-mediated maintenance of immune homeos

170 a13SR2 is not constitutively associated with talin in unactivated platelets, but becomes bound to tal

171 In contrast, mice lacking talins in the developing ureteric bud developed kidney a

172 ing node at newly formed adhesion sites in a talin-independent manner.

173 Talin induces allosteric rearrangements in integrins tha

174 nostaining experiments showed that vinculin, talin, integrin alpha(M)beta(2), and other components of

175 consists of the actin cytoskeleton-vinculin-talin-integrin-ligand-extracellular matrix-substrate for

176 sialylation, thus altering the regulation of talin/integrin/FAK/paxillin and integrin/NFkappaB signal

177 ntional binary binding conditions, the Rap1b/talin interaction becomes strong upon attachment of acti

178 pressing a talin1 mutant (W359A) that blocks talin interaction with integrins.

179 ed the role of kindlin as an enhancer of the talin interaction with the membrane proximal region of b

180 Talin interacts with beta-integrin tails and actin to co

181 inculin binding, activating ABS2 and locking talin into an actin-binding configuration that stabilize

182 sient by nature, probably due to the lack of talin involvement in FAK activation and the absence of v

183 Talin is a critical adhesion protein and participates in

184 Talin is a focal adhesion protein that is known to exten

185 Talin is a large 235-kDa protein composed of an N-termin

186 Talin is a major actin-binding protein that controls bot

187 Talin is a ubiquitous, large focal adhesion protein that

188 molecule relative to integrins suggest that talin is able to sense different force vectors, either p

189 Thus, although talin is an essential, shared regulator of all integrin

190 Talin is an integrin adaptor, which controls integrin ac

191 Talin is an intracellular protein that is critical for l

192 vation of transmembrane receptor integrin by talin is essential for inducing cell adhesion.

193 Tension on talin is increased by vinculin and depends mainly on act

194 the C-terminal actin-binding site (ABS3) in talin is required for adhesion complex assembly, the cen

195 Unlike vinculin, talin is under lower tension on soft substrates.

196 lecular details of the functions of specific talin isoforms in cell adhesion.

197 Activated by talin, it interacts with diverse adhesome components, en

198 We propose that the talin-KANK1 interaction links the two macromolecular ass

199 specific calpain-resistant point-mutants of talin (L432G) and FAK (V744G), we find that calpain inhi

200 These studies reveal the importance of talin-mediated activation of integrins for renal ischemi

201 logical force range of only a few pNs in the talin-mediated force transmission pathway.

202 Although the molecular details of talin-mediated integrin activation are known, the mechan

203 ing requires talin recruitment to integrins, talin-mediated integrin activation is dispensable.

204 inin and filamin can directly interfere with talin-mediated integrin activation.

205 ons are mechanosensitive structures in which talin mediates a linkage to actin filaments either direc

206 over, disruption of the MRL protein-integrin-talin (MIT) complex markedly impairs cell protrusion.

207 model to investigate vinculin activation by talin modulated by tensile force generated by transient

208 rization model, the rod domain region of one talin molecule binds to the F3 lobe on an adjacent talin

209 The different arrangements of the talin molecule relative to integrins suggest that talin

210 molecule binds to the F3 lobe on an adjacent talin molecule, thus achieving the state of autoinhibiti

211 vo Specifically, an autoinhibition-defective talin mutant strengthens and stabilizes integrin-based a

212 By expressing structure-based talin mutants in talin null cells, we show that while th

213 We find that neither talin nor vinculin alone recruit actin filaments to the

214 expressing structure-based talin mutants in talin null cells, we show that while the C-terminal acti

215 Our data indicate that docking by talin of the chemokine-activated alpha4beta1 to the acti

216 Hence, talin operates as a mechanical band-pass filter, able to

217 Without talin or actin polymerization, few early adhesions form,

218 ganization was normalized by reexpression of talin or integrin activating talin head domain but not a

219 re we report that fibroblasts lacking either talin or kindlin failed to activate beta1 integrins, adh

220 Loss of PIPKIgamma or talin or their interaction impaired EMT and the acquisit

221 We demonstrate that talin plays a key structural role in regulating the nano

222 talin head, the integrin-binding segment in talin, possesses a typical FERM-domain sequence, a trunc

223 d thrombus formation, and thus regulation of talin presents a critical node where pharmacological int

224 n, we measure the folding dynamics of single talin proteins in response to external mechanical noise

225 talin confirm the mechanosensory role of the talin R3 subdomain and exclude the possibility that the

226 further show that neutrophil arrest requires talin recruitment to and activation of integrins.

227 r, although neutrophil slow rolling requires talin recruitment to integrins, talin-mediated integrin

228 Talin recruitment to the membrane is necessary for its b

229 PIPKIgamma and talin regulate the stability of E-cadherin transcription

230 G protein (Galpha13) directly interacts with talin, relieves its state of autoinhibition, and trigger

231 However, differential stiffness sensing by talin requires ABS2 but not vinculin or ABS3.

232 The partial function of some mutant talins requires vinculin, indicating that recruitment of

233 The cooperation of kindlin with talin results in a complete disruption of salt bridges b

234 sign of vinculin activation by surface-bound talin revealed that clustered vinculin can initiate and

235 ix adhesions and results in the formation of talin-rich but unstable adhesions.

236 effects of molecular targeting (fibronectin, talin, ROCK), including 'adaptive switching' between Con

237 Mutation of the integrin binding site in the talin rod decreases cluster size.

238 he conserved KN domain in KANK1 binds to the talin rod domain R7.

239 dy provides evidence into how the controlled talin rod domain unfolding acts as a key regulator of ad

240 endent stochastic unfolding and refolding of talin rod domains make talin a very effective force buff

241 dent unfolding and refolding kinetics of all talin rod domains.

242 nstrate that stepwise destabilization of the talin rod R3 subdomain decreases cellular traction force

243 BXD suggest that the intermediate states in talin rod subdomains are stabilized by force during unfo

244 Force induced unfolding of talin rod subdomains has been proposed to act as a cellu

245 rovide free energy profiles for unfolding of talin rod subdomains.

246 s (MD) simulations to study unfolding of the talin rod.

247 n to the membrane, which critically controls talin's action, remains elusive.

248 Flow-dependent force transfer required talin's C-terminal actin binding site, ABS3, but not vin

249 ) that perturbs activation without impairing talin's capacity to link integrins to actin and other pr

250 3 shows SR2 binds directly to the F3 lobe of talin's head domain and competes with the rod domain for

251 vinculin and actomyosin activity help change talin's orientation.

252 munohistochemical staining demonstrated that talin S425 phosphorylation is significantly increased in

253 Talins, scaffolding proteins that bind to the membrane p

254 green fluorescent protein-labeled actin and talin shows that P2X7 inhibition alters actin cytoskelet

255 We observed a connection between talin stability and the rate of cell migration and also

256 iew, we present the current understanding of talin structure, its relationship to binding partners, a

257 podial adhesions correlated with actin flow, talin tension in large adhesions further from the cell e

258 Using a fluorescence-based talin tension sensor (TS), we found that uniaxial stretc

259 e report the development and validation of a talin tension sensor.

260 upstream of components such as integrins and talin that are regulated by both Radil and RIAM.

261 s, we identify the key functional domains of Talin that mediate its response to force.

262 sequence encoding the N-terminal fragment of talin (the talin head domain) with a subsequent insertio

263 t and activate talin, and the membrane-bound talin then activates vinculin.

264 nt a mechanistic basis for the regulation of talin through Galpha13.

265 Talin (tln) binds and activates integrins to couple extr

266 ubiquitously expressed cytoskeletal protein talin (Tln) is a component of muscle costameres that lin

267 p1-mediated membrane-targeting mechanism for talin to activate integrin.

268 hosphorylation of Akt and the recruitment of talin to beta1 integrins.

269 PKIgamma couples with a cytoskeletal protein talin to control the acquisition of mesenchymal phenotyp

270 dicating that recruitment of vinculin allows talin to duplicate its own activities.

271 migration, by Ezh2 disrupted the binding of talin to F-actin and thereby promoted the turnover of ad

272 fingers.' Formation of the complex requires talin to form a bridge between the MRL protein and the i

273 p1 effector that mediates the recruitment of talin to integrins, thereby supporting their activation.

274 Binding of the cytoskeletal adaptor protein talin to the beta-integrin cytoplasmic domain is a key f

275 pid binding in talin1 disrupt the binding of talin to the membrane, focal adhesion formation, and cel

276 However, the pathway that recruits talin to the membrane, which critically controls talin's

277 lecule (RIAM) followed by the recruitment of talin to the plasma membrane.

278 PIPKIgamma and talin together control the adhesion and phosphoinositide

279 cidate these processes, we measured force on talin together with actin flow speed.

280 cs of force fluctuation during stretching of talin under physiologically relevant pulling speeds and

281 ternative mechanisms of talin function, with talin using one or both of its integrin-binding sites.

282 Actin cytoskeleton-linked proteins such as talin, vinculin and filamin function as mechanosensors i

283 ntain the expected molecular markers such as talin, vinculin, and p130Cas, and they require talin for

284 Talin, vinculin, and paxillin are core components of the

285 t propose a critical role for forces driving talin-vinculin association, our data show that force-ind

286 an intermediate state stabilized by partial talin-vinculin association.

287 Activation of the talin-vinculin axis subsequently leads to the engagement

288 on the results of in vitro reconstitution of talin-vinculin-actin assemblies using synthetic membrane

289 Talin was found to be approximately 97 nm in length and

290 After FlnA KD, tension on talin was polarized in the direction of stretch, while F

291 at least one kindlin-encoding gene, whereas talin was present in several premetazoan lineages.

292 other adhesion molecules, alpha-actinin and talin, were also significantly slower in the presence of

293 action, including a single point mutation in talin, which disrupts KANK1 binding but not the talin fu

294 sed by structure-function studies is whether talin, which is critical for all integrin-mediated adhes

295 In accord with this prediction, we find that Talin, which links membrane and cortex, forms such a fro

296 s on elastic substrates increased tension on talin, which was unexpectedly independent of the orienta

297 onment using exquisite force sensors such as talin, whose folding status triggers mechanotransduction

298 atelets exhibited reduced co-localization of talin with alphaIIbbeta3, and reduced irreversible fibri

299 und to talin and promoted the interaction of talin with beta1A-integrin.

300 Recombinant analogs of talin with modified lengths recapitulated its polarized