Oncogenic rearrangements of the NTRK1/NGF receptor
ABSTRACT 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.
- SourceAvailable from: Jie Chen
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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  . Phosphorylation at Y490 "
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 · 2.06 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 . It is known that ligand-induced activation of TrkA induces its ubiquitination and subsequent degradation , but ubiquitin ligases that mediate TrkA ubiquitination have remained unknown until recently when Arévalo et al.  0014-5793/$36.00 "
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 · 3.34 Impact Factor
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- "No RET/PTC1, -2 or -3 rearrangements were identified in PTC. However, as other rearrangements involving the RET (Ciampi et al, 2007) or NTRK1 (Pierotti and Greco, 2006) genes have also been described in PTC, we specifically analysed RET and NTRK1 microarray mRNA expression in PTC negative for mutations. In one cPTC (sample 2 – Supplementary Table 1), a 20-fold increase in RET expression was detected in comparison to the other samples. "
ABSTRACT: Poorly differentiated thyroid carcinomas (PDTC) represent a heterogeneous, aggressive entity, presenting features that suggest a progression from well-differentiated carcinomas. To elucidate the mechanisms underlying such progression and identify novel therapeutic targets, we assessed the genome-wide expression in normal and tumour thyroid tissues. Microarray analyses of 24 thyroid carcinomas - 7 classic papillary, 8 follicular variants of papillary (fvPTC), 4 follicular (FTC) and 5 PDTC - were performed and correlated with RAS, BRAF, RET/PTC and PAX8-PPARG alterations. Selected genes were validated by quantitative RT-PCR in an independent set of 28 thyroid tumours. Unsupervised analyses showed that gene expression similarity was higher between PDTC and fvPTC, particularly for tumours harbouring RAS mutations. Poorly differentiated thyroid carcinomas presented molecular signatures related to cell proliferation, poor prognosis, spindle assembly checkpoint and cell adhesion. Compared with normal tissues, PTC had 307 out of 494 (60%) genes over-expressed, FTC had 137 out of 171 (80%) genes under-expressed, whereas PDTC had 92 out of 107 (86%) genes under-expressed, suggesting that gene downregulation is involved in tumour dedifferentiation. Significant UHRF1 and ITIH5 deregulated gene expression in PDTC, relatively to normal tissues, was confirmed by quantitative RT-PCR. Our findings suggest that fvPTC are possible precursors of PDTC. Furthermore, UHRF1 and ITIH5 have a potential therapeutic/prognostic value for aggressive thyroid tumours.British Journal of Cancer 10/2009; 101(10):1782-91. DOI:10.1038/sj.bjc.6605340 · 4.82 Impact Factor