Insulin-like growth factor-binding protein 1 stimulates human trophoblast migration by signaling through α5β1 integrin via mitogen-activated protein kinase pathway

LM Gleeson, C Chakraborty… - The Journal of Clinical …, 2001 - academic.oup.com
LM Gleeson, C Chakraborty, T McKinnon, PK Lala
The Journal of Clinical Endocrinology & Metabolism, 2001academic.oup.com
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 α5β1 integrin. We had shown that α5β1 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 …
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 α5β1 integrin. We had shown that α5β1 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 α5β1 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-α5β1 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 α5β1 integrin, leading to activation of FAK and stimulation of MAPK pathway.
Oxford University Press