Abstract
Urokinase-type plasminogen activator (uPA) participates in diverse (patho)physiological processes through intracellular signaling events that affect cell adhesion, migration, and proliferation, although the mechanisms by which these occur are only partially understood. Here we report that upon cell binding and internalization, single-chain uPA (scuPA) translocates to the nucleus within minutes. Nuclear translocation does not involve proteolytic activation or degradation of scuPA. Neither the urokinase receptor (uPAR) nor the low-density lipoprotein-related receptor (LRP) is required for nuclear targeting. Rather, translocation involves the binding of scuPA to the nucleocytoplasmic shuttle protein nucleolin through a region containing the kringle domain. RNA interference and mutational analysis demonstrate that nucleolin is required for the nuclear transport of scuPA. Furthermore, nucleolin is required for the induction smooth muscle alpha-actin (alpha-SMA) by scuPA. These data reveal a novel pathway by which uPA is rapidly translocated to the nucleus where it might participate in regulating gene expression.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / genetics
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Actins / metabolism
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Active Transport, Cell Nucleus
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Animals
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Base Sequence
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Cells, Cultured
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Gene Expression Regulation
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HeLa Cells
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Humans
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Kinetics
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LDL-Receptor Related Proteins / metabolism
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Mice
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Nucleolin
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Phosphoproteins / antagonists & inhibitors
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Phosphoproteins / chemistry
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Phosphoproteins / genetics
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Phosphoproteins / metabolism
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Protein Binding
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Protein Structure, Tertiary
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RNA Interference
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Small Interfering / genetics
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / chemistry
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RNA-Binding Proteins / genetics
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RNA-Binding Proteins / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sequence Deletion
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Signal Transduction
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Transfection
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Urokinase-Type Plasminogen Activator / chemistry
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Urokinase-Type Plasminogen Activator / genetics
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Urokinase-Type Plasminogen Activator / metabolism*
Substances
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Actins
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LDL-Receptor Related Proteins
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Phosphoproteins
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RNA, Messenger
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RNA, Small Interfering
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RNA-Binding Proteins
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Recombinant Proteins
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Urokinase-Type Plasminogen Activator