Activation of ERK signaling upon alternative protease nexin-1 internalization mediated by syndecan-1.
Protease nexin-1 (PN-1), an inhibitor of serine proteases, contributes to tissue homeostasis and influences the behavior of some tumor cells. The internalization of PN-1 protease complexes is considered to be mediated by the low-density lipoprotein receptor related protein 1 (LRP1). In this study, both wild-type and LRP1-/- mouse embryonic fibroblasts (MEF) were shown to internalize PN-1. Receptor associated protein (RAP) interfered with PN-1 uptake only in wild-type MEF cells, indicating that another receptor mediates PN-1 uptake in the absence of LRP1. In LRP1-/- MEF cells, inhibitor sensitivity and kinetic values (t(1/2) at 45 min) of PN-1 uptake showed a similarity to syndecan-1-mediated endocytosis. In these cells, PN-1 uptake was increased by overexpression of full-length syndecan-1 and decreased by RNA interference targeting this proteoglycan. Most important, in contrast to PKA activation known to be triggered by LRP1-mediated internalization, our study shows that syndecan-1-mediated internalization of PN-1 stimulated the Ras-ERK signaling pathway.
Li
Xiaobiao
X
Friedrich Miescher Institute for Biomedical Research, CH-4058, Basel, Switzerland.
Herz
Joachim
J
Monard
Denis
D
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D058255:Protease Nexins; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D058258:Serpin E2; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D019812:Heparan Sulfate Proteoglycans; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D058255:Protease Nexins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; C545486:SERPINE2 protein, human; D058258:Serpin E2; D053668:Syndecan-1; D025521:Tumor Suppressor Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D013917:Thrombin; D018631:ras Proteins