The NTRK1 gene encodes the high affinity receptor for Nerve Growth Factor, and its action regulates neural development and differentiation. Deregulation of NTRK1 activity is associated with several human disorders. Loss of function mutations cause the genetic disease Congenital Insensitivity to Pain with Anhidrosis (CIPA). Constitutive activation of NTRK1 has been detected in several tumor types. An autocrine loop involving NTRK1 and NGF is responsible for tumor progression in prostate carcinoma and in breast cancer. Somatic rearrangements of NTRK1, producing chimeric oncogenes with constitutive tyrosine kinase activity, have been detected in a consistent fraction of papillary thyroid tumors.
The topic of this review is the thyroid TRK oncogenes; the modalities of activation, the mechanism of action, and the contribution of activating sequences will be discussed.
NTRK1 (also known as TRKA) is the prototype of a family of genes which also includes NTRK2 (TRKB) and NTRK3 (TRKC), encoding tyrosine kinase receptors for the neurotrophins of the Nerve Growth Factor (NGF) family. NGF is the preferred ligand for NTRK1, brain-derived neurotrophic factor and NT4/5 are ligands for NTRK2, and NT3 is the ligand for NTRK3. Interestingly, NT3 is also capable of binding to NTRK1 and NTRK2, although with low affinity (Barbacid, M., 1995).
All the neurotrophins bind also the p75 low affinity receptor, which belongs to the TNF receptor family, and is devoid of kinase activity (Kaplan, D. R. et al., 2000).
Neurotrophins are responsible for the survival, differentiation and maintenance of specific population of neurons in the developing and adult nervous system (Davies, A. M., 1994). In particular, the NGF/NTRK1 signaling supports survival and differentiation of sympathetic and sensory neurons responsive to temperature and pain. In addition to its neurotrophic functions, NGF also stimulates proliferation of a number of cell types such as lymphocytes, keratinocytes and prostate cells (Otten, U., et al., 1989; Di Marco, E. et al., 1993; Djakiew, D. et al., 1991).
NTRK1 was originally isolated from a human colon carcinoma as a transforming oncogene activated by a somatic rearrangement that fused a non-muscle tropomyosin gene to a novel tyrosine kinase receptor (Martin-Zanca, D. et al., 1986). Cloning of the full length gene (Martin-Zanca, D. et al., 1989) and identification of the NGF as a ligand occurred few years later (Kaplan, D. R. et al., 1991).
The NTRK1 gene is located on chromosome 1q21-22 (Weier, H.-U. G. et al.,
1995) and consists of 17 exons distributed within a 25 kb region (Greco, A. et al.,
1996). The NTRK1 receptor is a glycosylated protein of 140 kDa, comprising an extracellular portion, including Ig-like and Leucine rich domains for ligand binding, a single transmembrane region, a juxta-membrane domain, a tyrosine kinase domain and a C-terminal tail. Following NGF binding, NTRK1 undergoes dimerization and autophosphorylation of five tyrosine residues (Y490, Y670, Y674, Y675, and Y785). Activated receptor initiates several signal transduction cascades, including the Mitogen Activated Protein Kinase (MAPK), the phosphatidylinositol 3-kinase (PI3K) and the PLC-y pathways. These signaling cascades culminate in the activation of transcription factors that alter gene expression (Kaplan, D. R. et al., 2000).
Deregulation of NTRK1 activity is associated with several human diseases. Mutations affecting different NTRK1 domains are associated with CIPA (Congenital Insensitiv-ity to Pain with Anhidrosis), a rare recessive genetic disease characterized by loss of pain and temperature sensation, defects in thermal regulation and occasionally mental retardation (Indo, Y. et al., 1996). CIPA is the consequence of a genetic defect in the differentiation and migration of neural crest elements. By studying the effects of different CIPA mutations on NTRK1 biochemical and biological properties, the molecular mechanisms responsible for the disease have been unveiled. CIPA mutations cause inactivation of the NTRK1 receptor by at least three different mechanisms, such as complete inactivation, protein processing alteration, and reduction of receptor activity (Greco, A. et al., 1999; Greco, A. et al., 2000; Miranda, C. et al., 2002a; Miranda, C. et al., 2002b).
NTRK1 gain of function mutations have been described in some human tumors. Activation through genomic rearrangements producing chimeric oncogenes has been detected in a consistent fraction of human papillary thyroid carcinoma, and it will be described later. A 75 amino acids deletion in the extracellular domain of the NTRK1 receptor, resulting in a mutated protein with in vitro transforming activity, has been detected in a patient with acute myeloid leukaemia, indicating that constitutive activation of the NTRK1 receptor may contribute to leukemogenesis (Reuther, G. W. et al., 2000). In human neuroblastoma, expression of NTRK1 is a good prognostic marker, suggesting that lack of NTRK1 expression contributes to malignancy, presumably because it results in the loss of signaling pathways important for growth arrest and/or differentiation of the neural crest derived cells from which these tumors originate (Brodeur, G. M. et al., 1997). In prostatic carcinoma an autocrine loop involving NGF and NTRK1 is responsible for tumor progression (Djakiew, D. et al., 1991), and tumor growth can be blocked by NTRK1 kinase inhibitors (Weeraratna, A. T. et al., 2001). Recently, an autocrine NGF/NTRK1 loop has been demonstrated in breast cancer cells, suggesting that it could represent a potential therapeutic target (Descamps, S. et al., 2001). It is interesting to outline that, at variance with other RTKs such as Met, FGFR, Kit and RET, no oncogenic activation ofNTRK1 by point mutations have been found in human cancer. Moreover, the introduction of missense mutations releasing the oncogenic potential of different RTKs showed a distinct effect on NTRK1 receptor. This suggests that, despite the high degree of conservation of certain amino acid residues, the NTRK1 receptor diverges from other RTKs in terms of tridimensional structure and have a distinct auto-inhibitory mechanism (Miranda, C. et al., 2002c).
Papillary thyroid carcinoma (PTC) is the most frequent neoplasia originating from the thyroid epithelium, and accounts for about 80% of all thyroid cancers (Hedinger, C. et al., 1988). A consistent fraction (50%) of PTC harbors chromosomal alterations causing somatic rearrangements, and consequent oncogenic activation, of two RTK genes, namely RET and NTRK1 (Pierotti, M. A. et al., 1996). For a long time RET and NTRK1 rearrangements represented the only known genetic alterations in PTC. Recently, mutations of BRAF, alternative to RTK rearrangements, have been reported by different groups, and they represent the most frequent alteration in PTC (Kimura, E. T. et al., 2003; Cohen, Y. et al., 2003; Soares, P. et al., 2003).
Both RET and TRK oncogenes have been discovered in our laboratory by DNA transfection/focus formation assay in NIH3T3 cells, starting from papillary thyroid tumor DNA. Transforming activity correlated with the presence of human RET and TRK sequences in the mouse transfectants DNA (Bongarzone, I. et al., 1989); this provided the basis for the isolation and characterization of the chimeric oncogenes, containing the receptor tyrosine kinase domain preceded by activating sequences from different genes.
Several TRK oncogenes have been isolated from thyroid tumors, differing in the activating genes (Figure 1). The TRK oncogene, identical to that first isolated from colon carcinoma, and containing sequences from the TPM3 gene on chromosome 1q22-23 (Wilton, S. D. et al, 1995), has been frequently found in thyroid tumors (Butti, M. G. et al., 1995). TRK-T1 and TRK-T2 derive both from rearrangement between NTRK1 and TPR gene on chromosome 1q25 (Miranda, C. et al, 1994); however, they display different structure, especially for the different TPR portion
MET TRK-T1 TRK-T2
MET TRK-T1 TRK-T2
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