Abstract
NTAK (neural- and thymus-derived activator for ErbB kinases), also known as neuregulin-2, is a member of the epidermal growth factor (EGF) family, which binds directly to ErbB3 and ErbB4 and transactivates ErbB2. Because ErbB signaling has been implicated in various angiogenic mechanisms, the effect of NTAK (which has at least nine isoforms due to alternative splicing) in angiogenesis is explored. One isoform, NTAKgamma, inhibited cell growth in terms of DNA synthesis and cell numbers in vascular endothelial cells specifically, whereas NTAKalpha and beta had no activity. On the other hand, NTAKgamma secreted by transfected MDA-MB-231 cells inhibited endothelial cell growth, and NTAKgamma expressed in endothelial cells by adenovirus infection suppressed cell growth in a dose-dependent manner. The EGF-like domain of NTAKgamma did not have this activity. The NTAKdelta isoform, which had the Ig-like domain but not the EGF-like domain, inhibited proliferation of endothelial cells. NTAKdelta prevented hyper-phosphorylation of the retinoblastoma tumor suppressor protein and caused G(1) arrest in endothelial cells. Both NTAKgamma and delta isoforms displayed anti-angiogenic activity in the chick embryo chorioallantoic membrane in vivo. These results suggest that the active site of NTAK is localized outside of the EGF-like domain but within the N-terminal region, including the Ig-like domain, of NTAK.
Highlights
Members of the ErbB family of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR or ErbB1), ErbB2, ErbB3, and ErbB4 (1– 4), are important mediators of cell growth, differentiation, and survival (5, 6)
To examine the effect of NTAK on angiogenesis, we examined three isoforms, NTAK␣, , and ␥, whose structures differ in their EGF-like domain (Fig. 1)
NTAK␥ had no effects on the growth of smooth muscle cells (SMCs), T47D cells, MDA-MB-453 cells, or SK-N-SH cells (Fig. 2C)
Summary
Members of the ErbB family of receptor tyrosine kinases, including epidermal growth factor receptor (EGFR or ErbB1), ErbB2 (neu), ErbB3, and ErbB4 (1– 4), are important mediators of cell growth, differentiation, and survival (5, 6). NTAK␥, inhibited cell growth in terms of DNA synthesis and cell numbers in vascular endothelial cells whereas NTAK␣ and  had no activity. The NTAK␦ isoform, which had the Ig-like domain but not the EGF-like domain, inhibited proliferation of endothelial cells.
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