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Molecular and Cellular Biology, November 2002, p. 7512-7523, Vol. 22, No. 21
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.21.7512-7523.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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

Shi Pan, Ping An, Rong Zhang, Xiangrong He, Guoyong Yin, and Wang Min*

Center for Cardiovascular Research, University of Rochester Medical Center, Rochester, New York 14642

Received 8 March 2002/ Returned for modification 29 April 2002/ Accepted 8 August 2002

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.

* Corresponding author. Mailing address: Center for Cardiovascular Research, University of Rochester Medical Center, 601 Elmwood Ave., Box 679, Rochester, NY 14642. Phone: (585) 273-1499. Fax: (585) 275-9895. E-mail: wang.min{at}rochester.edu.

Molecular and Cellular Biology, November 2002, p. 7512-7523, Vol. 22, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.21.7512-7523.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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