ReviewRearrangements of NTRK1 gene in papillary thyroid carcinoma
Section snippets
Molecular mechanisms underlying oncogenic NTRK1 rearrangements
Fig. 1 shows the chromosomal localization and transcriptional orientation of NTRK1 and its rearranging partners: TPM3, TPR on chromosome 1q, and TFG on chromosome 3q. The type of chromosomal rearrangement generating TRK oncogenes is not documented, since no cytogenetic studies on PTCs carrying NTRK1 rearrangements are available. A t(1;3)(q21;q11) translocation is most likely responsible for the generation of TRK-T3 oncogene (TFG/NTRK1 rearrangement). For TRK, TRK-T1 and TRK-T2, involving
NTRK1 receptor and TRK oncoproteins: structure and function
NTRK1, the high affinity receptor for NGF, is a member of the neurotrophin receptor family which also includes NTRK2 and NTRK3, binding to BDNF and NT3, respectively (Kaplan et al., 1991, Klein et al., 1991).
The NTRK1 receptor (Fig. 4) is a glycosylated protein of 140 kDa, comprising an extracellular portion, including Ig-like and leucine-rich domains for ligand binding, a single transmembrane domain, a juxta-membrane region, a tyrosine-kinase domain and a C-terminal tail. Following NGF binding,
Role of activating sequences in TRK oncogenic activation
The capability of TPM3, TPR and TFG to activate chimeric tyrosine-kinase oncogenes is not restricted TRK oncogenes; in fact, they have been found fused to other kinase genes. Both TPM3 and TFG were reported to fuse to ALK receptor gene in anaplastic large cell lymphoma (Hernandez et al., 2002, Lamant et al., 1999); moreover, TFG is rearranged with NOR1 in extraskeletal myxoid chondrosarcoma (Hisaoka et al., 2004). TPR was first identified in N-methyl-N′-nitro-N-nitrosoguanidine
Conclusions
Although occurring less frequently than RET rearrangements and BRAFV600E mutation, rearrangements of NTRK1 provide a useful model for studying the molecular basis of thyroid carcinogenesis. Studies performed almost exclusively in our laboratory have defined the mechanisms responsible for NTRK1 oncogenic rearrangements, and identified the molecular players involved in the process of TRK oncogenes transformation. Studies on TRK activating sequences have led to the identification of a novel gene,
Acknowledgements
This work is supported by AIRC (Associazione Italiana Ricerca Cancro), ACC (Alleanza Contro il Cancro), Ministry of Health. The Authors thanks Mrs. Cristina Mazzadi for secretarial help.
References (62)
- et al.
Molecular analysis of the RET and NTRK1 gene rearrangements in papillary thyroid carcinoma in the Polish population
Mutat. Res.
(2006) - et al.
A sequence analysis of the genomic regions involved in the rearrangements between TPM3 and NTRK1 genes producing TRK oncogenes in papillary thyroid carcinomas
Genomics
(1995) - et al.
ced-4 and proto-oncogene tfg-1 antagonistically regulate cell size and apoptosis in C. elegans
Curr. Biol.
(2008) - et al.
Nerve growth factor binds to normal human keratinocytes through high and low affinity receptors and stimulates their growth by a novel autocrine loop
J. Biol. Chem.
(1993) - et al.
Characterization of the NTRK1 genomic region involved in chromosomal rearrangements generating TRK oncogenes
Genomics
(1993) - et al.
Diversity of genomic breakpoints in TFG-ALK translocations in anaplastic large cell lymphomas: identification of a new TFG-ALK(XL) chimeric gene with transforming activity
Am. J. Pathol.
(2002) - et al.
Neurotrophin signal transduction in the nervous system
Curr. Opin. Neurobiol.
(2000) - et al.
The trk proto-oncogene encodes a receptor for nerve growth factor
Cell
(1991) - et al.
A new fusion gene TPM3-ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation
Blood
(1999) - et al.
ETV3-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages
Semin. Cancer Biol.
(2005)