Cancer Letters

Cancer Letters

Volume 169, Issue 2, 28 August 2001, Pages 107-114
Cancer Letters

Mini review
Trk receptor tyrosine kinases: A bridge between cancer and neural development

https://doi.org/10.1016/S0304-3835(01)00530-4Get rights and content

Abstract

The proto-oncogene Trks encode the high-affinity receptor tyrosine kinases for neurotrophins of a nerve growth factor (NGF) family. The Trk signals spatiotemporally regulate neural development and maintenance of neural network. However, Trk was originally cloned as an oncogene fused with the tropomyosin gene in the extracellular domain. Accumulating evidence has demonstrated that the rearranged Trk oncogene is often observed in non-neuronal neoplasms such as colon and papillary thyroid cancers, while the signals through the receptors encoded by the proto-oncogene Trks regulate growth, differentiation and apoptosis of the tumors with neuronal origin such as neuroblastoma and medulloblastoma. The intracellular Trk signaling pathway is also different depending on the Trk family receptors, cell types and the grade of transformation. Furthermore, developmentally programmed cell death of neuron, which is largely regulated by neurotrophin signaling, is at least in part controlled by tumor suppressors p53 and p73 as well as their antagonist ΔNp73. Thus, the Trks and their downstream signaling function in both ontogenesis and oncogenesis. In this short review, the dynamic role of the Trk family receptors signaling in neural development, neurogenic tumors and other cancers will be discussed.

Introduction

Trk is a receptor tyrosine kinase which primarily regulates growth, differentiation and programmed cell death of neurons in both peripheral and central nervous systems. The Trk gene, however, has originally been cloned as an oncogene fused with the tropomyosin gene in the extracellular domain, conferring constitutive activation of its tyrosine kinase activity to induce continuous proliferation of the cell. It was a great surprise when proto-oncogene Trk was found to be a high-affinity receptor for nerve growth factor (NGF) which plays a key role in regulating differentiation and programmed cell death during neural development. Nevertheless, the molecular basis of NGF/Trk signaling and its role in cancer have long been mysterious especially in neoplasms of nervous system such as neuroblastoma and medulloblastoma.

The recent investigations have just started to unveil the fact that NGF/Trk signaling is regulated by connecting a variety of intracellular signaling cascades which include protein products encoded by proto-oncogenes and tumor suppressor genes, most of which are indispensable for both neural development and tumorigenesis. In this review, the role of the oncogene Trk as well as that of the proto-oncogene Trk in human cancers is discussed in conjunction with the recent observations which link them to other cancer-related genes, p53 and p73.

Section snippets

Trk signaling regulates neuronal survival and differentiation

The discovery by Rita Levi-Montalcini and Vitor Hamburger of nerve growth factor (NGF) more than four decades ago has opened the door to understanding important role of soluble factors and their receptors in normal ontogeny [1]. However, the NGF function has not been unveiled until the proto-oncogene TrkA was found to encode the high-affinity receptor [2], [3]. The other NGF receptor was identified as p75NTR which bound to NGF with low affinity [4]. Now, neurotrophin family of growth factors

Trk as an oncogene

The Trk onocogene was one of the first transforming genes identified in human cancers [7]. The first Trk oncogene isolated from colon carcinoma was a fusion with the tropomyosin gene in the extracellular domain of the TrkA gene which rendered constitutive activation in the tyrosine kinase activity. The similar oncogenic rearrangement of the TrkA gene was found in thyroid papillary carcinomas with higher frequency [8] as well as in acute myeloid leukemia [9]. The systematic analysis done by

Proto-oncogene Trks functioning in cancers

In contrast to the Trk oncogenes with genomic DNA rearrangement or mutation which might directly contribute to tumorigenesis, the proto-oncogene Trk was also shown to play a role in regulating important biology of cancers especially with neuronal or neuroendocrine origin (Table 1).

The first evidence was reported in neuroblastoma (NBL), one of the most common pediatric neoplasms, which possesses enigmatic biology in different subset of the tumor. The high levels of prototype TrkA was expressed

Trk signaling in cancer cells

The Trk receptors are abnormal not only in their structure or expression levels but also in their intracellular signaling in cancerous cells. Most of the studies about Trk signaling have been performed using PC12 rat pheochromocytoma cell line which responds to NGF by inducing differentiation and growth arrest. The recent reports suggest that differentiation signals by NGF of the PC12 cells may be mediated through tyrosine phosphorylation of the Trk receptor and subsequent activation of

Trk signals meet with p53 and p73

The neurotrophin signaling through the Trk receptor activation can be segregated into three intracellular signaling pathways: inhibition of programmed cell death (PCD, apoptosis), induction of growth arrest and promotion of neuritogenesis. The recent lines of evidence have suggested that both p53 tumor suppressor protein and its related protein p73 are involved in the induction of PCD and growth arrest in neuronal cells [29]. p73 is a recently identified candidate tumor suppressor whose gene is

Future directions

In this short review, I discussed about the role of Trk receptor signaling in both normal neurons and cancer cells. The distance between the cell membrane, where Trk receptor tyrosine kinase locates, and the nucleus, where many transcription factor complexes are functioning, is not so far as we imagined some years ago. In the future, we further need to know what regulates or even developmentally programs the timing of expression of Trks in vivo, how the Trk signals control neuritogenesis and

Acknowledgements

The author would like to thank Toshinori Ozaki, Masato Takahashi and Shigeru Sakiyama for critical reading of the manuscript.

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