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Etk/Bmx as a Tumor Necrosis Factor Receptor Type 2-Specific Kinase: Role in Endothelial Cell Migration and Angiogenesis

Pan, Shi and An, Ping and Zhang, Rong and He, Xiangrong and Yin, Guoyong and Min, Wang (2002) Etk/Bmx as a Tumor Necrosis Factor Receptor Type 2-Specific Kinase: Role in Endothelial Cell Migration and Angiogenesis. Molecular and Cellular Biology, 22 (21). 7512 - 7523. ISSN 0270-7306

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Abstract

<jats:title>ABSTRACT</jats:title> <jats:p>Tumor necrosis factor (TNF) is a cytokine that mediates many pathophysiologial processes, including angiogenesis. However, the molecular signaling involved in TNF-induced angiogenesis has not been determined. In this study, we examined the role of Etk/Bmx, an endothelial/epithelial tyrosine kinase involved in cell adhesion, migration, and survival in TNF-induced angiogenesis. We show that TNF activates Etk specifically through TNF receptor type 2 (TNFR2) as demonstrated by studies using a specific agonist to TNFR2 and TNFR2-deficient cells. Etk forms a preexisting complex with TNFR2 in a ligand-independent manner, and the association is through multiple domains (pleckstrin homology domain, TEC homology domain, and SH2 domain) of Etk and the C-terminal domain of TNFR2. The C-terminal 16-amino-acid residues of TNFR2 are critical for Etk association and activation, and this Etk-binding and activating motif in TNFR2 is not overlapped with the TNFR-associated factor type 2 (TRAF2)-binding sequence. Thus, TRAF2 is not involved in TNF-induced Etk activation, suggesting a novel mechanism for Etk activation by cytokine receptors. Moreover, a constitutively active form of Etk enhanced, whereas a dominant-negative Etk blocked, TNF-induced endothelial cell migration and tube formation. While most TNF actions have been attributed to TNFR1, our studies demonstrate that Etk is a TNFR2-specific kinase involved in TNF-induced angiogenic events.</jats:p>


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Pan, Shi
An, Pingpia1@pitt.eduPIA10000-0002-3080-2288
Zhang, Rong
He, Xiangrong
Yin, Guoyong
Min, Wang
Date: November 2002
Date Type: Publication
Journal or Publication Title: Molecular and Cellular Biology
Volume: 22
Number: 21
Publisher: American Society for Microbiology
Page Range: 7512 - 7523
DOI or Unique Handle: 10.1128/mcb.22.21.7512-7523.2002
Schools and Programs: Dietrich School of Arts and Sciences > Biological Sciences
Refereed: Yes
ISSN: 0270-7306
Date Deposited: 31 May 2018 14:53
Last Modified: 13 Jun 2021 07:55
URI: http://d-scholarship.pitt.edu/id/eprint/34565

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