Tenascin-C induction by cyclic strain requires integrin-linked kinase.
Induction of tenascin-C mRNA by cyclic strain in fibroblasts depends on RhoA and Rho dependent kinase (ROCK). Here we show that integrin-linked kinase (ILK) is required upstream of this pathway. In ILK-deficient fibroblasts, RhoA was not activated and tenascin-C mRNA remained low after cyclic strain; tenascin-C expression was unaffected by ROCK inhibition. In ILK wild-type but not ILK-/- fibroblasts, cyclic strain-induced reorganization of actin stress fibers and focal adhesions, as well as nuclear translocation of MAL, a transcriptional co-activator that links actin assembly to gene expression. These findings support a role for RhoA in ILK-mediated mechanotransduction. Rescue of ILK -/- fibroblasts by expression of wild-type ILK restored these responses to cyclic strain. Mechanosensation is not entirely abolished in ILK -/- fibroblasts, since cyclic strain activated Erk-1/2 and PKB/Akt, and induced c-fos mRNA in these cells. Conversely, lysophosphatidic acid stimulated RhoA and induced both c-fos and tenascin-C mRNA in ILK -/- cells. Thus, the signaling pathways controlling tenascin-C expression are functional in the absence of ILK, but are not triggered by cyclic strain. Our results indicate that ILK is selectively required for the induction of specific genes by mechanical stimulation via RhoA-mediated pathways.
Maier
Silke
S
Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, CH-4058 Basel, Switzerland.
Lutz
Roman
R
Gelman
Laurent
L
Sarasa-Renedo
Ana
A
Schenk
Susanne
S
Grashoff
Carsten
C
Chiquet
Matthias
M
D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015151:Immunoblotting; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009185:Myelin Proteins / Q000378:metabolism; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011510:Proteolipids / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D019063:Tenascin / Q000096:biosynthesis* / Q000235:genetics; D013718:Tensile Strength; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000099200:Scaffold Protein ILK
D008246:Lysophospholipids; D026901:Membrane Transport Proteins; D009185:Myelin Proteins; D062806:Myelin and Lymphocyte-Associated Proteolipid Proteins; D017346:Protein Serine-Threonine Kinases; D011510:Proteolipids; D051057:Proto-Oncogene Proteins c-akt; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D019063:Tenascin; D020742:rhoA GTP-Binding Protein; D000099200:Scaffold Protein ILK; C569027:Mal protein, mouse; C032881:lysophosphatidic acid