The tyrosine kinase Fer is a downstream target of the PLD-PA pathway that regulates cell migration.
Phosphatidic acid (PA), which can be produced by phospholipase D (PLD), is involved in various signaling events, such as cell proliferation, survival, and migration. However, the molecular mechanisms that link PA to cell migration are largely unknown. Here, we show that PA binds to the tyrosine kinase Fer and enhances its ability to phosphorylate cortactin, a protein that promotes actin polymerization. We found that a previously unknown lipid-binding module in Fer adjacent to the F-BAR [Fes-Cdc42-interacting protein 4 (CIP4) homology (FCH) and bin-amphiphysin-Rvs] domain mediated PA binding. We refer to this lipid-binding domain as the FX (F-BAR extension) domain. Overexpression of Fer enhanced lamellipodia formation and cell migration in a manner dependent on PLD activity and the PA-FX interaction. Thus, the PLD-PA pathway promotes cell migration through Fer-induced enhancement of actin polymerization.
Itoh
Toshiki
T
Division of Membrane Biology, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo, Japan. titoh@med.kobe-u.ac.jp
Hasegawa
Junya
J
Tsujita
Kazuya
K
Kanaho
Yasunori
Y
Takenawa
Tadaomi
T
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D051356:Cortactin / Q000235:genetics / Q000378:metabolism; D006801:Humans; D010712:Phosphatidic Acids / Q000235:genetics / Q000378:metabolism*; D010739:Phospholipase D / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism
D000199:Actins; D051356:Cortactin; D010712:Phosphatidic Acids; C052602:proto-oncogene protein c-fes-fps; D011505:Protein-Tyrosine Kinases; D010739:Phospholipase D