Expression and function of TRK-B and BDNF in human neuroblastomas.
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.
Nakagawara
A
A
Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110.
Azar
C G
CG
Scavarda
N J
NJ
Brodeur
G M
GM
D019208:Brain-Derived Neurotrophic Factor; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002648:Child; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020801:Receptor, Ciliary Neurotrophic Factor; D020917:Receptor, trkA; D017978:Receptors, Growth Factor / Q000235:genetics* / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D019208:Brain-Derived Neurotrophic Factor; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D020801:Receptor, Ciliary Neurotrophic Factor; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA