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

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.

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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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    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 [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 · 3.34 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. "
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    British Journal of Cancer 10/2009; 101(10):1782-91. DOI:10.1038/sj.bjc.6605340 · 4.82 Impact Factor
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