P311-induced myofibroblasts exhibit ameboid-like migration through RalA activation.
We previously showed that P311, an intracellular protein involved in cell migration, is found in human wound myofibroblast precursors (proto-myofibroblasts) and myofibroblasts. Furthermore, by binding to the TGF-beta1 latency associated protein (LAP), P311 induced NIH 3T3 cells to transform into non-fibrogenic myofibroblasts characterized by lack of TGF-beta1 production. Here we demonstrate that P311-induced myofibroblasts migrate in an ameboid rather than a mesenchymal pattern. Ameboid migration is characterized by lack of focal adhesions and stress fibers, absence of integrins and MMPs clustering/activation and changes in small GTPases activity, all leading to increased cell motility. P311-induced ameboid migration depended on activation of the GTPase RalA and was reverted to mesenchymal-type migration by RalA RNA interference. Ameboid migration was conserved in cells plated on fibrin, the initial wound matrix, but was switched back to mesenchymal-type migration by collagen I, the main ECM component in late stages of wound healing. TGF-beta1, the major stimulus of collagen production during wound repair, also reversed the ameboid phenotype to mesenchymal. Our studies therefore suggest that, by inducing RalA activity, P311 promotes a motile proto-myofibroblast and myofibroblast phenotype specifically adapted to rapidly populate the initial wound matrix.
Shi
Jinghua
J
Department of Pathology, Wayne State University, School of Medicine, Detroit, MI 48201, USA.
Badri
Kameswara Rao
KR
Choudhury
Ranginee
R
Schuger
Lucia
L
D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010641:Phenotype; D034622:RNA Interference; D014162:Transfection; D014945:Wound Healing / Q000502:physiology*; D020725:ral GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D009419:Nerve Tissue Proteins; D020725:ral GTP-Binding Proteins