Oncogenic rearrangements of the NTRK1/NGF receptor

Department of Experimental Oncology and Labs Operative Unit 3, Istituto Nazionale Tumori, Via G. Venezian, 1 20133 Milan, Italy.
Cancer Letters (Impact Factor: 5.62). 02/2006; 232(1):90-8. DOI: 10.1016/j.canlet.2005.07.043
Source: PubMed


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 causes 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 associated with tumor progression in prostate carcinoma and in breast cancer. A novel alternative splicing variant with constitutive oncogenic potential has been recently described in neuroblastoma. 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 a detailed analysis of the thyroid TRK oncogenes. The modalities of their activation, their mechanism of action, the contribution of activating sequences, and the molecular mechanisms underlying their generation will be discussed.

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    • "Of those, we are particularly interested in NGF-TrkA and BDNF-TrkB signaling pathways. TrkA regulates proliferation and is important for development and maturation of the nervous system [16] [20]. Phosphorylation at Y490 "
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    ABSTRACT: Intracerebral hemorrhage (ICH), accounting for 15–20% of strokes, can cause significant brain injury and life long neurological deficits. We investigated whether treadmill exercise rehabilitation could improve brain repair after ICH and whether involvement of NFG-TrkA and BDNF-TrkB signaling could be observed during repair period in an experimental mouse ICH model reproduced by heparinized-collagenase infusion into the left caudate putamen. 5-Bromo-2-deoxyuridine (BrdU) labeled new dividing cell can be observed clearly around the injured cortex and striatum region on day 7 (D7) after operation, and both TrkA and TrkB neurotropic receptors were activated. A subgroup of these ICH mice began the treadmill exercise from D4 after operation. Then we found that the overall immunofluorescent signals of p-Y490-TrkA and p-Y705-TrkB were both decreased in all groups at D14 after operation. However, compared to the non-exercise ICH group mouse, the immunofluorescent intensity of BDNF and p-Y705-TrkB were significantly higher in the exercise group. In addition, there was no difference in p-Y490-TrkA. Our results suggest that BDNF-TrkB but not NGF-TrkA signaling is involved in the brain repair after ICH, and early proper treadmill exercise might promote this repair process.
    Neuroscience Letters 10/2012; 529(1):28–32. DOI:10.1016/j.neulet.2012.09.021 · 2.03 Impact Factor
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    • "Nerve growth factor (NGF) receptor TrkA is also a member of the family of RTKs and belongs to a sub-family of protein kinases which also includes TrkB and TrkC. TrkA regulates neuronal cell proliferation and is important for development and maturation of the nervous system [13]. It is known that ligand-induced activation of TrkA induces its ubiquitination and subsequent degradation [14], but ubiquitin ligases that mediate TrkA ubiquitination have remained unknown until recently when Arévalo et al. [15] 0014-5793/$36.00 "
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    ABSTRACT: Nerve growth factor (NGF) binding to its receptor TrkA, which belongs to the family of receptor tyrosine kinases (RTKs), is known to induce its internalization, endosomal trafficking and subsequent lysosomal degradation. The Cbl family of ubiquitin ligases plays a major role in mediating ubiquitination and degradation of RTKs. However, it is not known whether Cbl participates in mediating ubiquitination of TrkA. Here we report that c-Cbl mediates ligand-induced ubiquitination and degradation of TrkA. TrkA ubiquitination and degradation required direct interactions between c-Cbl and phosphorylated TrkA. c-Cbl and ubiquitinated TrkA are found in a complex after NGF stimulation and are degraded in lysosomes. Taken together, our data demonstrate that c-Cbl can induce downregulation of NGF-TrkA complexes through ubiquitination and degradation of TrkA.
    FEBS letters 06/2011; 585(12):1741-7. DOI:10.1016/j.febslet.2011.04.056 · 3.17 Impact Factor
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    • "The MNA-specific p3/h3 group was also characterized by a very low expression of NTRK1, whereas the favorable tumour group p1/h1 showed the highest expression of NTRK1. TrkA (or NTRK1) is a well-known marker of favorable NB tumours and its expression has been linked to several cancer forms [56]. "
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    ABSTRACT: There are currently three postulated genomic subtypes of the childhood tumour neuroblastoma (NB); Type 1, Type 2A, and Type 2B. The most aggressive forms of NB are characterized by amplification of the oncogene MYCN (MNA) and low expression of the favourable marker NTRK1. Recently, mutations or high expression of the familial predisposition gene Anaplastic Lymphoma Kinase (ALK) was associated to unfavourable biology of sporadic NB. Also, various other genes have been linked to NB pathogenesis. The present study explores subgroup discrimination by gene expression profiling using three published microarray studies on NB (47 samples). Four distinct clusters were identified by Principal Components Analysis (PCA) in two separate data sets, which could be verified by an unsupervised hierarchical clustering in a third independent data set (101 NB samples) using a set of 74 discriminative genes. The expression signature of six NB-associated genes ALK, BIRC5, CCND1, MYCN, NTRK1, and PHOX2B, significantly discriminated the four clusters (p < 0.05, one-way ANOVA test). PCA clusters p1, p2, and p3 were found to correspond well to the postulated subtypes 1, 2A, and 2B, respectively. Remarkably, a fourth novel cluster was detected in all three independent data sets. This cluster comprised mainly 11q-deleted MNA-negative tumours with low expression of ALK, BIRC5, and PHOX2B, and was significantly associated with higher tumour stage, poor outcome and poor survival compared to the Type 1-corresponding favourable group (INSS stage 4 and/or dead of disease, p < 0.05, Fisher's exact test). Based on expression profiling we have identified four molecular subgroups of neuroblastoma, which can be distinguished by a 6-gene signature. The fourth subgroup has not been described elsewhere, and efforts are currently made to further investigate this group's specific characteristics.
    Cancer Cell International 04/2011; 11(1):9. DOI:10.1186/1475-2867-11-9 · 2.77 Impact Factor
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