Requirement of TGF-β Receptor-Dependent Activation of c-Jun N-Terminal Kinases (JNKs)/Stress-Activated Protein Kinases (Sapks) for TGF-β Up-Regulation of the Urokinase-Type Plasminogen Activator Receptor

Jianbo Yue, Baodong Sun, Guangming Liu, Kathleen Mulder

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Abstract

We have previously demonstrated that activation of the Ras/Mapk pathways is required for transforming growth factor β (TGF-β) induction of TGF-β1 expression. Here we examined the role of the Ras/Mapk pathways in TGF-β induction of urokinase-type plasminogen activator receptor (uPAR) expression in untransformed intestinal epithelial cells (IECs). TGF-β activated the stress-activated protein kinases (Sapk)/c-Jun N-terminal kinases (JNKs) within 5-10 min, an effect that preceeded TGF-β induction of uPAR expression in these cells. TGF-β induction of both JNK1 activity and JunD phosphorylation was blocked by expression of a dominant-negative mutant of the type II TGF-β receptor (DN TβRII), a dominant-negative mutant of MKK4 (DN MKK4), or a dominant-negative mutant of Ras (RasN17), or by the addition of the JNK inhibitor SP600125. TGF-β also induced AP-1 complex formation at the distal AP-1 site (-184 to -178) of the uPAR promoter within 2 h of TGF-β addition, consistent with the time-dependent up-regulation of uPAR expression. The primary components present in the TGF-β-stimulated AP-1 complex bound to the uPAR promoter were Jun D and Fra-2. Moreover, addition of SP600125, or expression of DN MKK4 or DN TβRII, blocked TGF-β up-regulation of uPAR in IECs. Accordingly, our results indicate that TGF-β activates the Ras/MKK4/JNK1 signaling cascade, leading to induction of AP-1 activity, which, in turn, up-regulates uPAR expression. Our results also indicate that the type II TGF-β receptor (RII) is required for TGF-β activation of JNK1 and the resulting up-regulation of uPAR expression.

Original languageEnglish (US)
Pages (from-to)284-292
Number of pages9
JournalJournal of Cellular Physiology
Volume199
Issue number2
DOIs
StatePublished - May 1 2004

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Urokinase Plasminogen Activator Receptors
Growth Factor Receptors
JNK Mitogen-Activated Protein Kinases
Transforming Growth Factors
Heat-Shock Proteins
Protein Kinases
Up-Regulation
Chemical activation
Transcription Factor AP-1
Epithelial Cells
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

@article{4468a4bd47914fa5baf6c81a4853bffb,
title = "Requirement of TGF-β Receptor-Dependent Activation of c-Jun N-Terminal Kinases (JNKs)/Stress-Activated Protein Kinases (Sapks) for TGF-β Up-Regulation of the Urokinase-Type Plasminogen Activator Receptor",
abstract = "We have previously demonstrated that activation of the Ras/Mapk pathways is required for transforming growth factor β (TGF-β) induction of TGF-β1 expression. Here we examined the role of the Ras/Mapk pathways in TGF-β induction of urokinase-type plasminogen activator receptor (uPAR) expression in untransformed intestinal epithelial cells (IECs). TGF-β activated the stress-activated protein kinases (Sapk)/c-Jun N-terminal kinases (JNKs) within 5-10 min, an effect that preceeded TGF-β induction of uPAR expression in these cells. TGF-β induction of both JNK1 activity and JunD phosphorylation was blocked by expression of a dominant-negative mutant of the type II TGF-β receptor (DN TβRII), a dominant-negative mutant of MKK4 (DN MKK4), or a dominant-negative mutant of Ras (RasN17), or by the addition of the JNK inhibitor SP600125. TGF-β also induced AP-1 complex formation at the distal AP-1 site (-184 to -178) of the uPAR promoter within 2 h of TGF-β addition, consistent with the time-dependent up-regulation of uPAR expression. The primary components present in the TGF-β-stimulated AP-1 complex bound to the uPAR promoter were Jun D and Fra-2. Moreover, addition of SP600125, or expression of DN MKK4 or DN TβRII, blocked TGF-β up-regulation of uPAR in IECs. Accordingly, our results indicate that TGF-β activates the Ras/MKK4/JNK1 signaling cascade, leading to induction of AP-1 activity, which, in turn, up-regulates uPAR expression. Our results also indicate that the type II TGF-β receptor (RII) is required for TGF-β activation of JNK1 and the resulting up-regulation of uPAR expression.",
author = "Jianbo Yue and Baodong Sun and Guangming Liu and Kathleen Mulder",
year = "2004",
month = "5",
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doi = "10.1002/jcp.10469",
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volume = "199",
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journal = "Journal of Cellular Physiology",
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T1 - Requirement of TGF-β Receptor-Dependent Activation of c-Jun N-Terminal Kinases (JNKs)/Stress-Activated Protein Kinases (Sapks) for TGF-β Up-Regulation of the Urokinase-Type Plasminogen Activator Receptor

AU - Yue, Jianbo

AU - Sun, Baodong

AU - Liu, Guangming

AU - Mulder, Kathleen

PY - 2004/5/1

Y1 - 2004/5/1

N2 - We have previously demonstrated that activation of the Ras/Mapk pathways is required for transforming growth factor β (TGF-β) induction of TGF-β1 expression. Here we examined the role of the Ras/Mapk pathways in TGF-β induction of urokinase-type plasminogen activator receptor (uPAR) expression in untransformed intestinal epithelial cells (IECs). TGF-β activated the stress-activated protein kinases (Sapk)/c-Jun N-terminal kinases (JNKs) within 5-10 min, an effect that preceeded TGF-β induction of uPAR expression in these cells. TGF-β induction of both JNK1 activity and JunD phosphorylation was blocked by expression of a dominant-negative mutant of the type II TGF-β receptor (DN TβRII), a dominant-negative mutant of MKK4 (DN MKK4), or a dominant-negative mutant of Ras (RasN17), or by the addition of the JNK inhibitor SP600125. TGF-β also induced AP-1 complex formation at the distal AP-1 site (-184 to -178) of the uPAR promoter within 2 h of TGF-β addition, consistent with the time-dependent up-regulation of uPAR expression. The primary components present in the TGF-β-stimulated AP-1 complex bound to the uPAR promoter were Jun D and Fra-2. Moreover, addition of SP600125, or expression of DN MKK4 or DN TβRII, blocked TGF-β up-regulation of uPAR in IECs. Accordingly, our results indicate that TGF-β activates the Ras/MKK4/JNK1 signaling cascade, leading to induction of AP-1 activity, which, in turn, up-regulates uPAR expression. Our results also indicate that the type II TGF-β receptor (RII) is required for TGF-β activation of JNK1 and the resulting up-regulation of uPAR expression.

AB - We have previously demonstrated that activation of the Ras/Mapk pathways is required for transforming growth factor β (TGF-β) induction of TGF-β1 expression. Here we examined the role of the Ras/Mapk pathways in TGF-β induction of urokinase-type plasminogen activator receptor (uPAR) expression in untransformed intestinal epithelial cells (IECs). TGF-β activated the stress-activated protein kinases (Sapk)/c-Jun N-terminal kinases (JNKs) within 5-10 min, an effect that preceeded TGF-β induction of uPAR expression in these cells. TGF-β induction of both JNK1 activity and JunD phosphorylation was blocked by expression of a dominant-negative mutant of the type II TGF-β receptor (DN TβRII), a dominant-negative mutant of MKK4 (DN MKK4), or a dominant-negative mutant of Ras (RasN17), or by the addition of the JNK inhibitor SP600125. TGF-β also induced AP-1 complex formation at the distal AP-1 site (-184 to -178) of the uPAR promoter within 2 h of TGF-β addition, consistent with the time-dependent up-regulation of uPAR expression. The primary components present in the TGF-β-stimulated AP-1 complex bound to the uPAR promoter were Jun D and Fra-2. Moreover, addition of SP600125, or expression of DN MKK4 or DN TβRII, blocked TGF-β up-regulation of uPAR in IECs. Accordingly, our results indicate that TGF-β activates the Ras/MKK4/JNK1 signaling cascade, leading to induction of AP-1 activity, which, in turn, up-regulates uPAR expression. Our results also indicate that the type II TGF-β receptor (RII) is required for TGF-β activation of JNK1 and the resulting up-regulation of uPAR expression.

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U2 - 10.1002/jcp.10469

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VL - 199

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JO - Journal of Cellular Physiology

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