Nakagawara A, Azar C G, Scavarda N J, Brodeur G M
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
Mol Cell Biol. 1994 Jan;14(1):759-67. doi: 10.1128/mcb.14.1.759-767.1994.
There is considerable interest in the role of the TRK family of neuotrophin receptors in regulating growth and differentiation in normal and neoplastic nerve cells. A neuroblastoma is a common pediatric tumor derived from the neural crest, and the majority of favorable neuroblastomas express a high level of TRK-A mRNA. However, little is known about the expression or function of TRK-B in these tumors. TRK-B encodes a tyrosine kinase that binds to brain-derived neuotrophic factor (BDNF), as well as neurotrophin-3 (NT-3) and NT-4/5. We have studied the N-myc-amplified human neuroblastoma cell line, SMS-KCN, which expresses both TRK-B and BDNF. Exogenous BDNF induces tyrosine phosphorylation of TRK-B as well as phosphorylation of phospholipase C-gamma 1, the extracellular signal-regulated kinases 1 and 2, and phosphatidylinositol-3 kinase. BDNF also induces expression of the immediate-early genes c-FOS and NGFI-A but not NGFI-B or NGFI-C. In addition, BDNF appears to promote cell survival and neurite outgrowth. SMS-KCN cells also express TRK-A, which is phosphorylated in response to nerve growth factor. However, the downstream TRK-A signaling is apparently defective. Finally, we determined that in a series of 74 primary neuroblastomas, 36% express TRK-B mRNA, 68% express BDNF mRNA, and 31% express both. Truncated TRK-B appears to be preferentially expressed in more-differentiated tumors (ganglioneuromas and ganglioneuroblastomas), whereas full-length TRK-B is expressed almost exclusively in immature neuroblastomas with N-myc amplification. Our findings suggest that in TRK-B-expressing human neuroblastomas, BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine manner. The BDNF/TRK-B pathway may be particularly important for growth and differentiation of neuroblastomas with N-myc amplification.
神经营养因子受体TRK家族在调节正常和肿瘤性神经细胞的生长及分化过程中的作用备受关注。神经母细胞瘤是一种常见的源自神经嵴的儿科肿瘤，大多数预后良好的神经母细胞瘤表达高水平的TRK-A mRNA。然而，关于TRK-B在这些肿瘤中的表达或功能却知之甚少。TRK-B编码一种酪氨酸激酶，它能与脑源性神经营养因子（BDNF）、神经营养因子-3（NT-3）以及NT-4/5结合。我们研究了N-myc扩增的人神经母细胞瘤细胞系SMS-KCN，该细胞系同时表达TRK-B和BDNF。外源性BDNF可诱导TRK-B的酪氨酸磷酸化以及磷脂酶C-γ1、细胞外信号调节激酶1和2以及磷脂酰肌醇-3激酶的磷酸化。BDNF还可诱导即刻早期基因c-FOS和NGFI-A的表达，但不诱导NGFI-B或NGFI-C的表达。此外，BDNF似乎能促进细胞存活和神经突生长。SMS-KCN细胞也表达TRK-A，其可响应神经生长因子而发生磷酸化。然而，TRK-A的下游信号传导显然存在缺陷。最后，我们确定在一系列74例原发性神经母细胞瘤中，36%表达TRK-B mRNA，68%表达BDNF mRNA，31%两者均表达。截短的TRK-B似乎在分化程度更高的肿瘤（神经节神经瘤和神经节神经母细胞瘤）中优先表达，而全长TRK-B几乎仅在伴有N-myc扩增的未成熟神经母细胞瘤中表达。我们的研究结果表明，在表达TRK-B的人神经母细胞瘤中，BDNF以自分泌或旁分泌方式促进存活并诱导神经突生长。BDNF/TRK-B通路对于伴有N-myc扩增的神经母细胞瘤的生长和分化可能尤为重要。
