title: Insulin-like growth factor-binding protein 1 stimulates human trophoblast migration by signaling through alpha 5 beta 1 integrin via mitogen-activated protein Kinase pathway.
abstract: A highly migratory subpopulation of the human placental trophoblast, known as the extravillous trophoblast (EVT), invades the uterus and its vasculature, to establish adequate exchange of key molecules between the maternal and fetal circulations. During their formation, EVT cells selectively acquire alpha 5 beta 1 integrin. We had shown that alpha 5 beta 1 is required for their migratory function, and that EVT cell migration is stimulated by insulin-like growth factor-binding protein (IGFBP)-1 produced by the uterine decidua. The present study examined whether this stimulation is dependent on binding of the Arg-Gly-Asp (RGD) domain of IGFBP-1 to an RGD binding site on the alpha 5 beta 1 integrin, followed by activation of focal adhesion kinase (FAK) and stimulation of the mitogen-activated protein kinase (MAPK) pathway. IGFBP-1 treatment increased migration of EVT cells, whereas an anti-alpha 5 beta 1 integrin antibody blocked migration regardless of IGFBP-1 treatment. Migration stimulation by IGFBP-1 was abrogated by pretreatment with a Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP), but not a Gly-Arg-Gly-Glu-Ser-Pro (GRGESP) hexapeptide, and by mutation of the RGD domain of IGFBP-1 to Trp-Gly-Asp (WGD). IGFBP-1 treatment caused a rapid localization of immunoreactive FAK to cellular lamellipodia, a rapid increase in phosphorylation of FAK and extracellular-signal regulated kinases 1 and 2. Preincubation of EVT cells with Herbimycin A, a tyrosine kinase inhibitor, abrogated IGFBP-1 effects; whereas an MAPK kinase inhibitor, PD 98059, reduced migration regardless of IGFBP-1 treatment. These results indicate that IGFBP-1 stimulation of EVT cell migration occurs by binding of its RGD domain to the alpha 5 beta 1 integrin, leading to activation of FAK and stimulation of MAPK pathway.
authors.affiliation: Department of Anatomy and Cell Biology, The University of Western Ontario, London, Ontario, Canada N6C 5C1.
authors.forename: L M
authors.initials: LM
authors.lastname: Gleeson
authors.forename: C
authors.initials: C
authors.lastname: Chakraborty
authors.forename: T
authors.initials: T
authors.lastname: McKinnon
authors.forename: P K
authors.initials: PK
authors.lastname: Lala
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D016227:Benzoquinones; D016466:CHO Cells; D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D047029:Lactams, Macrocyclic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D009842:Oligopeptides / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology; D017469:Receptors, Fibronectin / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014018:Tissue Distribution; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*
chemical_list: D000906:Antibodies; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018970:Insulin-Like Growth Factor Binding Protein 1; D047029:Lactams, Macrocyclic; D009842:Oligopeptides; D011809:Quinones; D017469:Receptors, Fibronectin; D017828:Rifabutin; C020754:herbimycin; C047981:arginyl-glycyl-aspartic acid; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one