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Critical Role for TrkB Kinase Function in Anoikis Suppression, Tumorigenesis, and Metastasis

Division of Molecular Genetics, the Netherlands Cancer Institute, Amsterdam, the Netherlands

Requests for reprints: Daniel S. Peeper, Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam 1066 CX, the Netherlands. Phone: 31-20-512-2002; Fax: 11-31-20-512-2011; E-mail: d.peeper{at}nki.nl.

Anoikis, or cell death induced by cell detachment, provides protection against the metastatic spread of tumor cells. We have previously shown that the neurotrophic receptor tyrosine kinase TrkB suppresses anoikis in rat intestinal epithelial cells and renders them highly tumorigenic and metastatic. Because TrkB is overexpressed in several aggressive human cancers, first attempts are being made to target TrkB in cancer therapy. However, the mechanisms underlying TrkB-mediated anoikis suppression, tumorigenesis, and metastasis still remain largely elusive. Although, to date, most attempts to neutralize TrkB in tumors aim to inactivate its kinase activity, it is unclear whether TrkB kinase activity is required for its oncogenic functions. Indeed, it has been suggested that also other properties of the receptor contribute to functions that are relevant to tumor cell survival. Specifically, several adhesion motifs reside within the extracellular domains of TrkB. In line with this, TrkB-expressing epithelial cells form large cellular aggregates in suspension cultures, possibly facilitating tumor cell survival. Therefore, we set out to study the relative contributions of TrkB's kinase activity and its adhesion domains to anoikis suppression and oncogenicity. On the basis of a structure-function analysis, we report that TrkB kinase activity is required and, unexpectedly, also sufficient for anoikis suppression, tumor formation, and experimental metastasis. Thus, TrkB can act tumorigenically independent of its adhesion motifs. These results suggest that targeting the enzymatic activity of TrkB might be beneficial in cancer therapy. [Cancer Res 2007;67(13):6221–30]

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