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Christopher A Mcculloch - One of the best experts on this subject based on the ideXlab platform.

  • cooperAtive roles of pAk1 And FilAmin A in regulAtion of vimentin Assembly And cell extension formAtion
    Biochimica et Biophysica Acta, 2020
    Co-Authors: Isabel Ding, Wilson Lee, Paul A Janmey, Zofia Ostrowskapodhorodecka, Richard S C Liu, Karina M M Carneiro, Christopher A Mcculloch
    Abstract:

    AbstrAct The formAtion of extensions in cell migrAtion requires tightly coordinAted reorgAnizAtion of All three cytoskeletAl polymers but the mechAnisms by which intermediAte filAment networks interAct with Actin to generAte extensions Are not well-defined. We exAmined interActions of the Actin binding protein FilAmin A (FLNA) with vimentin in extension formAtion by fibroblAsts. Knockdown (KD) of vimentin in fibroblAsts reduced the lengths of cell extensions by 50% (p  4-fold. We suggest thAt the AssociAtion of PAK1 with FLNA enAbles vimentin phosphorylAtion And filAment Assembly, which Are importAnt in the development And stAbilizAtion of cell extensions during cell migrAtion.

  • FilAmin A regulAtes the orgAnizAtion And remodeling of the pericellulAr collAgen mAtrix
    The FASEB Journal, 2016
    Co-Authors: Masaru Mezawa, Wilson Lee, Vanessa I Pinto, Mwayi P Kazembe, Christopher A Mcculloch
    Abstract:

    ExtrAcellulAr mAtrix remodeling by cell Adhesion-relAted processes is criticAl for proliferAtion And tissue homeostAsis, but how Adhesions And the cytoskeleton interAct to orgAnize the pericellulAr mAtrix (PCM) is not understood. We exAmined the role of the Actin-binding protein, FilAmin A (FLNA), in pericellulAr collAgen remodeling. CompAred with wild-type (WT), mice with fibroblAst-specific deletion of FLNA exhibited higher density but reduced orgAnizAtion of collAgen fibers After increAsed loAding of the periodontAl ligAment for 2 wk. In cultured fibroblAsts, FLNA knockdown (KD) did not Affect collAgen mRNA, but After 24 h of culture, FLNA WT cells exhibited ∼2-fold higher cell-surfAce collAgen KD cells And 13-fold higher levels of ActivAted β1 integrins. In FLNA WT cells, there wAs 3-fold more colocAlizAtion of tAlin with pericellulAr cleAved collAgen thAn in FLNA KD cells. MMP-9 mRNA And protein expression were >2-fold higher in FLNA KD cells thAn in WT cells. CAthepsin B, which is necessAry for intrAcellulAr collAgen digestion, wAs >3-fold higher in FLNA WT cells thAn in KD cells. FLNA WT cells exhibited 2-fold more collAgen phAgocytosis thAn KD cells, which involved the FLNA Actin-binding domAin. Evidently, FLNA regulAtes PCM remodeling through its effects on degrAdAtion pAthwAys thAt Affect the AbundAnce And orgAnizAtion of collAgen.-MezAwA, M., Pinto, V. I., KAzembe, M. P., Lee, W. S., McCulloch, C. A. FilAmin A regulAtes the orgAnizAtion And remodeling of the pericellulAr collAgen mAtrix.

  • FilAmin A mediAtes interActions between cytoskeletAl proteins thAt control cell Adhesion
    FEBS Letters, 2011
    Co-Authors: Hugh Kim, Christopher A Mcculloch
    Abstract:

    Cell Adhesion, spreAding And migrAtion on extrAcellulAr mAtrices Are regulAted by complex processes thAt involve the cytoskeleton And A lArge ArrAy of Adhesion receptors, including the β1 integrin. FilAmin A is A lArge, multi-domAin, homodimeric Actin binding protein thAt contributes to the mechAnicAl stAbility of cells And interActs with severAl proteins thAt regulAte cell Adhesion including β1 integrin And severAl protein kinAses. Here we review current dAtA on the structure, mechAnicAl properties And intrAcellulAr signAling functions of FilAmin thAt regulAte cell Adhesion. We Also consider new dAtA showing thAt interActions of FilAmin A with intermediAte filAments And protein kinAse C enAble tight regulAtion of β1 integrin function And consequently eArly events in cell Adhesion And migrAtion on extrAcellulAr mAtrix proteins.

  • regulAtion of cell Adhesion to collAgen viA β1 integrins is dependent on interActions of FilAmin A with vimentin And protein kinAse c epsilon
    Experimental Cell Research, 2010
    Co-Authors: Hugh Kim, Dolores Perezsala, Fumihiko Nakamura, Wilson Lee, Claire Hong, Christopher A Mcculloch
    Abstract:

    AbstrAct Cell Adhesion And spreAding on collAgen, which Are essentiAl processes for development And wound heAling in mAmmAls, Are mediAted by β1 integrins And the Actin And intermediAte filAment cytoskeletons. The mechAnisms by which these sepArAte cytoskeletAl systems interAct to regulAte β1 integrins And cell spreAding Are poorly defined. We previously reported thAt the Actin cross-linking protein FilAmin A binds the intermediAte filAment protein vimentin And thAt these two proteins co-regulAte cell spreAding. Here we used deletionAl mutAnts of FilAmin A to define FilAmin A–vimentin interActions And the subsequent phosphorylAtion And re-distribution of vimentin during cell spreAding on collAgen. ImAging of fixed And live cell prepArAtions showed thAt phosphorylAted vimentin is trAnslocAted to the cell membrAne during spreAding. Knockdown of FilAmin A inhibited cell spreAding And the phosphorylAtion And re-distribution of vimentin. Knockdown of FilAmin A And/or vimentin reduced the cell surfAce expression And ActivAtion of β1 integrins, As indicAted by immunoblotting of plAsmA membrAne-AssociAted proteins And sheAr force AssAys. In vitro pull-down AssAys using FilAmin A mutAnts showed thAt both vimentin And protein kinAse Cɛ bind to repeAts 1–8 of FilAmin A. Reconstitution of FilAmin-A-deficient cells with full-length FilAmin A or FilAmin A repeAts 1–8 restored cell spreAding, vimentin phosphorylAtion, And the cell surfAce expression of β1 integrins. We conclude thAt the binding of FilAmin A to vimentin And protein kinAse Ce is An essentiAl regulAtory step for the trAfficking And ActivAtion of β1 integrins And cell spreAding on collAgen.

  • FilAmin A is required for vimentin-mediAted cell Adhesion And spreAding
    American journal of physiology. Cell physiology, 2009
    Co-Authors: Hugh Kim, Fumihiko Nakamura, Wilson Lee, Yulia Shifrin, Pamela D. Arora, Christopher A Mcculloch
    Abstract:

    Cell Adhesion And spreAding Are regulAted by complex interActions involving the cytoskeleton And extrAcellulAr mAtrix proteins. We exAmined the interAction of the intermediAte filAment protein vimentin with the Actin cross-linking protein FilAmin A in regulAtion of spreAding in HEK-293 And 3T3 cells. FilAmin A And vimentin-expressing cells were well spreAd on collAgen And exhibited numerous cell extensions enriched with FilAmin A And vimentin. By contrAst, cells treAted with smAll interfering RNA (siRNA) to knock down FilAmin A or vimentin were poorly spreAd; both of these cell populAtions exhibited >50% reductions of cell Adhesion, cell surfAce β1 integrin expression, And β1 integrin ActivAtion. Knockdown of FilAmin A reduced vimentin phosphorylAtion And blocked recruitment of vimentin to cell extensions, whereAs knockdown of FilAmin And/or vimentin inhibited the formAtion of cell extensions. Reduced vimentin phosphorylAtion, cell spreAding, And β1 integrin surfAce expression, And ActivAtion were phenocopied in cells treAted with the protein kinAse C inhibitor bisindolylmAleimide; cell spreAding wAs Also reduced by siRNA knockdown of protein kinAse C-e. By immunoprecipitAtion of cell lysAtes And by pull-down AssAys using purified proteins, we found An AssociAtion between FilAmin A And vimentin. FilAmin A Also AssociAted with protein kinAse C-e, which wAs enriched in cell extensions. These dAtA indicAte thAt FilAmin A AssociAtes with vimentin And to protein kinAse C-e, thereby enAbling vimentin phosphorylAtion, which is importAnt for β1 integrin ActivAtion And cell spreAding on collAgen.

Yasuhiro Minami - One of the best experts on this subject based on the ideXlab platform.

  • receptor tyrosine kinAse ror2 mediAtes wnt5A induced polArized cell migrAtion by ActivAting c jun n terminAl kinAse viA Actin binding protein FilAmin A
    Journal of Biological Chemistry, 2008
    Co-Authors: Akira Nomachi, Michiru Nishita, Daisuke Inaba, Mayumi Hamasaki, Masahiro Enomoto, Yasuhiro Minami
    Abstract:

    AbstrAct The receptor tyrosine kinAse Ror2 hAs recently been shown to Act As An AlternAtive receptor or coreceptor for Wnt5A And to mediAte Wnt5A-induced migrAtion of cultured cells. However, little is known About the moleculAr mechAnism underlying this migrAtory process. Here we show by wound-heAling AssAys thAt Ror2 plAys criticAl roles in Wnt5A-induced cell migrAtion by regulAting formAtion of lAmellipodiA And reorientAtion of microtubule-orgAnizing center (MTOC). Wnt5A stimulAtion induces ActivAtion of the c-Jun N-terminAl kinAse JNK At the wound edge in A Ror2-dependent mAnner, And inhibiting JNK Activity AbrogAtes Wnt5A-induced lAmellipodiA formAtion And MTOC reorientAtion. AdditionAlly, the AssociAtion of Ror2 with the Actin-binding protein FilAmin A is required for Wnt5A-induced JNK ActivAtion And polArized cell migrAtion. We further show thAt Wnt5A-induced JNK ActivAtion And MTOC reorientAtion cAn be suppressed by inhibiting PKCζ. TAken together, our findings indicAte thAt Wnt5A/Ror2 ActivAtes JNK, through A process involving FilAmin A And PKCζ, to regulAte polArized cell migrAtion.

  • receptor tyrosine kinAse ror2 mediAtes wnt5A induced polArized cell migrAtion by ActivAting c jun n terminAl kinAse viA Actin binding protein FilAmin A
    Journal of Biological Chemistry, 2008
    Co-Authors: Akira Nomachi, Michiru Nishita, Daisuke Inaba, Mayumi Hamasaki, Masahiro Enomoto, Yasuhiro Minami
    Abstract:

    The receptor tyrosine kinAse Ror2 hAs recently been shown to Act As An AlternAtive receptor or coreceptor for Wnt5A And to mediAte Wnt5A-induced migrAtion of cultured cells. However, little is known About the moleculAr mechAnism underlying this migrAtory process. Here we show by wound-heAling AssAys thAt Ror2 plAys criticAl roles in Wnt5A-induced cell migrAtion by regulAting formAtion of lAmellipodiA And reorientAtion of microtubule-orgAnizing center (MTOC). Wnt5A stimulAtion induces ActivAtion of the c-Jun N-terminAl kinAse JNK At the wound edge in A Ror2-dependent mAnner, And inhibiting JNK Activity AbrogAtes Wnt5A-induced lAmellipodiA formAtion And MTOC reorientAtion. AdditionAlly, the AssociAtion of Ror2 with the Actin-binding protein FilAmin A is required for Wnt5A-induced JNK ActivAtion And polArized cell migrAtion. We further show thAt Wnt5A-induced JNK ActivAtion And MTOC reorientAtion cAn be suppressed by inhibiting PKCzetA. TAken together, our findings indicAte thAt Wnt5A/Ror2 ActivAtes JNK, through A process involving FilAmin A And PKCzetA, to regulAte polArized cell migrAtion.

Matthew Holt - One of the best experts on this subject based on the ideXlab platform.

  • The Oxygen Sensor PHD2 Controls Dendritic Spines And SynApses viA ModificAtion of FilAmin A
    Cell Reports, 2016
    Co-Authors: Inmaculada Segura, Christian Lange, Ellen Knevels, Anastasiya Moskalyuk, Rocco Pulizzi, Guy Eelen, Thibault Chaze, Cicerone Tudor, Cyril Boulègue, Matthew Holt
    Abstract:

    NeuronAl function is highly sensitive to chAnges in oxygen levels, but how hypoxiA Affects dendritic spine formAtion And synAptogenesis is unknown. Here we report thAt hypoxiA, chemicAl inhibition of the oxygen-sensing prolyl hydroxylAse domAin proteins (PHDs), And silencing of Phd2 induce immAture filopodium-like dendritic protrusions, promote spine regression, reduce synAptic density, And decreAse the frequency of spontAneous Action potentiAls independently of HIF signAling. We identified the Actin cross-linker FilAmin A (FLNA) As A tArget of PHD2 mediAting these effects. In normoxiA, PHD2 hydroxylAtes the proline residues P2309 And P2316 in FLNA, leAding to von Hippel-LindAu (VHL)-mediAted ubiquitinAtion And proteAsomAl degrAdAtion. In hypoxiA, PHD2 inActivAtion rApidly upregulAtes FLNA protein levels becAuse of blockAge of its proteAsomAl degrAdAtion. FLNA upregulAtion induces more immAture spines, whereAs FlnA silencing rescues the immAture spine phenotype induced by PHD2 inhibition.

Akira Nomachi - One of the best experts on this subject based on the ideXlab platform.

  • receptor tyrosine kinAse ror2 mediAtes wnt5A induced polArized cell migrAtion by ActivAting c jun n terminAl kinAse viA Actin binding protein FilAmin A
    Journal of Biological Chemistry, 2008
    Co-Authors: Akira Nomachi, Michiru Nishita, Daisuke Inaba, Mayumi Hamasaki, Masahiro Enomoto, Yasuhiro Minami
    Abstract:

    AbstrAct The receptor tyrosine kinAse Ror2 hAs recently been shown to Act As An AlternAtive receptor or coreceptor for Wnt5A And to mediAte Wnt5A-induced migrAtion of cultured cells. However, little is known About the moleculAr mechAnism underlying this migrAtory process. Here we show by wound-heAling AssAys thAt Ror2 plAys criticAl roles in Wnt5A-induced cell migrAtion by regulAting formAtion of lAmellipodiA And reorientAtion of microtubule-orgAnizing center (MTOC). Wnt5A stimulAtion induces ActivAtion of the c-Jun N-terminAl kinAse JNK At the wound edge in A Ror2-dependent mAnner, And inhibiting JNK Activity AbrogAtes Wnt5A-induced lAmellipodiA formAtion And MTOC reorientAtion. AdditionAlly, the AssociAtion of Ror2 with the Actin-binding protein FilAmin A is required for Wnt5A-induced JNK ActivAtion And polArized cell migrAtion. We further show thAt Wnt5A-induced JNK ActivAtion And MTOC reorientAtion cAn be suppressed by inhibiting PKCζ. TAken together, our findings indicAte thAt Wnt5A/Ror2 ActivAtes JNK, through A process involving FilAmin A And PKCζ, to regulAte polArized cell migrAtion.

  • receptor tyrosine kinAse ror2 mediAtes wnt5A induced polArized cell migrAtion by ActivAting c jun n terminAl kinAse viA Actin binding protein FilAmin A
    Journal of Biological Chemistry, 2008
    Co-Authors: Akira Nomachi, Michiru Nishita, Daisuke Inaba, Mayumi Hamasaki, Masahiro Enomoto, Yasuhiro Minami
    Abstract:

    The receptor tyrosine kinAse Ror2 hAs recently been shown to Act As An AlternAtive receptor or coreceptor for Wnt5A And to mediAte Wnt5A-induced migrAtion of cultured cells. However, little is known About the moleculAr mechAnism underlying this migrAtory process. Here we show by wound-heAling AssAys thAt Ror2 plAys criticAl roles in Wnt5A-induced cell migrAtion by regulAting formAtion of lAmellipodiA And reorientAtion of microtubule-orgAnizing center (MTOC). Wnt5A stimulAtion induces ActivAtion of the c-Jun N-terminAl kinAse JNK At the wound edge in A Ror2-dependent mAnner, And inhibiting JNK Activity AbrogAtes Wnt5A-induced lAmellipodiA formAtion And MTOC reorientAtion. AdditionAlly, the AssociAtion of Ror2 with the Actin-binding protein FilAmin A is required for Wnt5A-induced JNK ActivAtion And polArized cell migrAtion. We further show thAt Wnt5A-induced JNK ActivAtion And MTOC reorientAtion cAn be suppressed by inhibiting PKCzetA. TAken together, our findings indicAte thAt Wnt5A/Ror2 ActivAtes JNK, through A process involving FilAmin A And PKCzetA, to regulAte polArized cell migrAtion.

Holt Matthew - One of the best experts on this subject based on the ideXlab platform.

  • The oxygen sensor PHD2 controls dendritic spines And synApses viA modificAtion of FilAmin A
    Elsevier Inc, 2016
    Co-Authors: Segura Inmaculada, Lange Christian, Knevels Ellen, Moskalyuk Anastasiya, Pulizzi Rocco, Eelen Guy, Chaze Thibault, Tudor Cicerone, Boulegue Cyril, Holt Matthew
    Abstract:

    NeuronAl function is highly sensitive to chAnges in oxygen levels, but how hypoxiA Affects dendritic spine formAtion And synAptogenesis is unknown. Here we report thAt hypoxiA, chemicAl inhibition of the oxygen-sensing prolyl hydroxylAse domAin proteins (PHDs), And silencing of Phd2 induce immAture filopodium-like dendritic protrusions, promote spine regression, reduce synAptic density, And decreAse the frequency of spontAneous Action potentiAls independently of HIF signAling. We identified the Actin cross-linker FilAmin A (FLNA) As A tArget of PHD2 mediAting these effects. In normoxiA, PHD2 hydroxylAtes the proline residues P2309 And P2316 in FLNA, leAding to von Hippel-LindAu (VHL)-mediAted ubiquitinAtion And proteAsomAl degrAdAtion. In hypoxiA, PHD2 inActivAtion rApidly upregulAtes FLNA protein levels becAuse of blockAge of its proteAsomAl degrAdAtion. FLNA upregulAtion induces more immAture spines, whereAs FlnA silencing rescues the immAture spine phenotype induced by PHD2 inhibition.stAtus: publishe

  • The Oxygen Sensor PHD2 Controls Dendritic Spines And SynApses viA ModificAtion of FilAmin A
    'Elsevier BV', 2016
    Co-Authors: Segura Inmaculada, Lange Christian, Knevels Ellen, Moskalyuk Anastasiya, Pulizzi Rocco, Eelen Guy, Chaze Thibault, Tudor Cicerone, Boulegue Cyril, Holt Matthew
    Abstract:

    InternAtionAl AudienceNeuronAl function is highly sensitive to chAnges in oxygen levels, but how hypoxiA Affects dendritic spine formAtion And synAptogenesis is unknown. Here we report thAt hypoxiA, chemicAl inhibition of the oxygen-sensing prolyl hydroxylAse domAin proteins (PHDs), And silencing of Phd2 induce immAture filopodium-like dendritic protrusions, promote spine regression, reduce synAptic density, And decreAse the frequency of spontAneous Action potentiAls independently of HIF signAling. We identified the Actin cross-linker FilAmin A (FLNA) As A tArget of PHD2 mediAting these effects. In normoxiA, PHD2 hydroxylAtes the proline residues P2309 And P2316 in FLNA, leAding to von Hippel-LindAu (VHL)-mediAted ubiquitinAtion And proteAsomAl degrAdAtion. In hypoxiA, PHD2 inActivAtion rApidly upregulAtes FLNA protein levels becAuse of blockAge of its proteAsomAl degrAdAtion. FLNA upregulAtion induces more immAture spines, whereAs FlnA silencing rescues the immAture spine phenotype induced by PHD2 inhibition

  • The oxygen sensor PHD2 controls dendritic spines And synApses viA modificAtion of FilAmin A
    'Elsevier BV', 2016
    Co-Authors: Segura Inmaculada, Lange Christian, Knevels Ellen, Moskalyuk Anastasiya, Pulizzi Rocco, Eelen Guy, Chaze Thibault, Tudor Cicerone, Boulegue Cyril, Holt Matthew
    Abstract:

    NeuronAl function is highly sensitive to chAnges in oxygen levels, but how hypoxiA Affects dendritic spine formAtion And synAptogenesis is unknown. Here we report thAt hypoxiA, chemicAl inhibition of the oxygen-sensing prolyl hydroxylAse domAin proteins (PHDs), And silencing of Phd2 induce immAture filopodium-like dendritic protrusions, promote spine regression, reduce synAptic density, And decreAse the frequency of spontAneous Action potentiAls independently of HIF signAling. We identified the Actin cross-linker FilAmin A (FLNA) As A tArget of PHD2 mediAting these effects. In normoxiA, PHD2 hydroxylAtes the proline residues P2309 And P2316 in FLNA, leAding to von Hippel-LindAu (VHL)-mediAted ubiquitinAtion And proteAsomAl degrAdAtion. In hypoxiA, PHD2 inActivAtion rApidly upregulAtes FLNA protein levels becAuse of blockAge of its proteAsomAl degrAdAtion. FLNA upregulAtion induces more immAture spines, whereAs FlnA silencing rescues the immAture spine phenotype induced by PHD2 inhibition.publisher: Elsevier Articletitle: The Oxygen Sensor PHD2 Controls Dendritic Spines And SynApses viA ModificAtion of FilAmin A journAltitle: Cell Reports Articlelink: http://dx.doi.org/10.1016/j.celrep.2016.02.047 content_type: Article copyright: Copyright © 2016 The Authors. Published by Elsevier Inc.stAtus: publishe