Mini reviewTrk receptor tyrosine kinases: A bridge between cancer and neural development
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.
References (40)
- et al.
The trk protooncogene encodes a receptor for nerve growth factor
Cell
(1991) Functions of the neurotrophins during nervous system development: What the knockouts are teaching us
Cell
(1994)- et al.
The trk family of tyrosine protein kinase receptors
Biochim. Biophys. Acta
(1991) - et al.
Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25)
Blood
(1999) - et al.
Fusion of EIV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25)
Blood
(1999) - et al.
Up-regulation of insulin-like growth factor-TI expression is a feature of TrkA but not IrkB activation in SH-SY5Y neuroblastoma
Am. J. Pathol.
(1999) - et al.
Apoptotic pathway induced by nerve growth factor-mediated TrkA activation in medulloblastoma
J. Biol. Chem.
(2000) - et al.
Nerve growth factor cooperates with pl85HER2 in activating growth of human breast carcinoma cells
J. Biol. Chem.
(2000) - et al.
Induction of neuronal differentiation by p73 in a neuroblastoma cell line
J. Biol. Chem.
(2000) - et al.
Mediation of nerve growth factor-driven cell cycle arrest in PC12 cells by p53 - Simultaneous differentiation and proliferation subsequent to p53 functional inactivation
J. Biol. Chem.
(2000)