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Synergistic induction of mitogen-activated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2.

Publication ,  Journal Article
Chandrasekharan, UM; Waitkus, M; Kinney, CM; Walters-Stewart, A; DiCorleto, PE
Published in: Arterioscler Thromb Vasc Biol
October 2010

OBJECTIVE: To determine the molecular mechanism underlying the synergistic response of mitogen-activated protein kinase phosphatase-1 (MKP-1), which is induced by thrombin and epidermal growth factor (EGF). METHODS AND RESULTS: MKP-1 induction by thrombin (approximately 6-fold) was synergistically increased (approximately 18-fold) by cotreatment with EGF in cultured endothelial cells. EGF alone did not induce MKP-1 substantially (<2-fold). The synergistic induction of MKP-1 was not mediated by matrix metalloproteinases. The EGF receptor kinase inhibitor AG1478 blocked approximately 70% of MKP-1 induction by thrombin plus EGF (from 18- to 6-fold) but not the response to thrombin alone. An extracellular signal-regulated kinase (ERK)-dependent protease-activated receptor-1 (PAR-1) signal was required for the thrombin alone effect; an ERK-independent PAR-1 signal was necessary for the approximately 12-fold MKP-1 induction by thrombin plus EGF. VEGF induction of MKP-1 was also approximately 12-fold and c-Jun N-terminal kinase (JNK) dependent. Inhibitors of extracellular signal-regulated kinase and JNK activation blocked thrombin plus EGF-induced MKP-1 completely. Furthermore, VEGF receptor 2 depletion blocked the synergistic response without affecting the induction of MKP-1 by thrombin alone. CONCLUSIONS: We have identified a novel signaling interaction between protease-activated receptor-1 and EGF receptor that is mediated by VEGF receptor 2 and results in synergistic MKP-1 induction.

Duke Scholars

Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

October 2010

Volume

30

Issue

10

Start / End Page

1983 / 1989

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Transcriptional Activation
  • Thrombin
  • Signal Transduction
  • Receptor, PAR-1
  • RNA, Messenger
  • Mice
  • Kinetics
  • Humans
  • HSP90 Heat-Shock Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chandrasekharan, U. M., Waitkus, M., Kinney, C. M., Walters-Stewart, A., & DiCorleto, P. E. (2010). Synergistic induction of mitogen-activated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2. Arterioscler Thromb Vasc Biol, 30(10), 1983–1989. https://doi.org/10.1161/ATVBAHA.110.212399
Chandrasekharan, Unni M., Matthew Waitkus, Corttrell M. Kinney, Alicia Walters-Stewart, and Paul E. DiCorleto. “Synergistic induction of mitogen-activated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2.Arterioscler Thromb Vasc Biol 30, no. 10 (October 2010): 1983–89. https://doi.org/10.1161/ATVBAHA.110.212399.
Chandrasekharan UM, Waitkus M, Kinney CM, Walters-Stewart A, DiCorleto PE. Synergistic induction of mitogen-activated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2. Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1983–9.
Chandrasekharan, Unni M., et al. “Synergistic induction of mitogen-activated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2.Arterioscler Thromb Vasc Biol, vol. 30, no. 10, Oct. 2010, pp. 1983–89. Pubmed, doi:10.1161/ATVBAHA.110.212399.
Chandrasekharan UM, Waitkus M, Kinney CM, Walters-Stewart A, DiCorleto PE. Synergistic induction of mitogen-activated protein kinase phosphatase-1 by thrombin and epidermal growth factor requires vascular endothelial growth factor receptor-2. Arterioscler Thromb Vasc Biol. 2010 Oct;30(10):1983–1989.

Published In

Arterioscler Thromb Vasc Biol

DOI

EISSN

1524-4636

Publication Date

October 2010

Volume

30

Issue

10

Start / End Page

1983 / 1989

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor Receptor-2
  • Transcriptional Activation
  • Thrombin
  • Signal Transduction
  • Receptor, PAR-1
  • RNA, Messenger
  • Mice
  • Kinetics
  • Humans
  • HSP90 Heat-Shock Proteins