P21-activated kinase 1: convergence point in PDGF- and LPA-stimulated collagen matrix contraction by human fibroblasts.
Fibroblast three-dimensional collagen matrix culture provides a tissue-like model that can be used to analyze cell form and function. The physiological agonists platelet-derived growth factor (PDGF) and lysophosphatidic acid (LPA) both stimulate human fibroblasts to contract floating collagen matrices. In this study, we show that the PDGF and LPA signaling pathways required for matrix contraction converge on p21-activated kinase 1 (PAK1) and its downstream effector cofilin1 and that contraction depends on cellular ruffling activity, rather than on the protrusion and retraction of cellular dendritic extensions. We also show that, depending on the agonist, different Rho effectors cooperate with PAK1 to regulate matrix contraction, Rho kinase in the case of PDGF and mDia1 in the case of LPA. These findings establish a unified framework for understanding the cell signaling pathways involved in fibroblast contraction of floating collagen matrices.
Rhee
Sangmyung
S
Department of Cell Biology, University of Texas Southwestern Medical School, Dallas, TX 75390, USA.
Grinnell
Frederick
F
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000235:genetics; D048430:Cell Shape / Q000187:drug effects; D022081:Cell Surface Extensions / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000080865:Formins; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D015739:Nocodazole / Q000494:pharmacology; D037342:Pertussis Toxin / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D054462:p21-Activated Kinases; D054460:rho-Associated Kinases
D048868:Adaptor Proteins, Signal Transducing; D002867:Chromones; D051338:Cofilin 1; C108962:DIAPH1 protein, human; D004791:Enzyme Inhibitors; D000080865:Formins; D047908:Intracellular Signaling Peptides and Proteins; D008246:Lysophospholipids; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D003094:Collagen; D037342:Pertussis Toxin; C515903:PAK1 protein, human; C515907:PAK2 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D054460:rho-Associated Kinases; C032881:lysophosphatidic acid; D015739:Nocodazole