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.
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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 · 2.06 Impact Factor
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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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ABSTRACT: Nuclear pore complexes (NPCs) composed of approximately 30 individual nucleoporins form huge macromolecular assemblies in the nuclear envelope, through which bidirectional cargo movement between the nucleus and cytoplasm occurs. Beyond their transport function, NPCs can serve as docking sites for chromatin and thereby contribute to the organization of the overall topology of chromosomes in conjunction with other factors of the nuclear envelope. Recent studies suggest that gene-NPC interactions may promote both transcription and the definition of heterochromatin-euchromatin boundaries. Intriguingly, several nucleoporins were linked to cancer, mostly in the context of chromosomal translocations, which encode nucleoporin chimeras. An emerging concept is that tumor cells exploit specific properties of nucleoporins to deregulate transcription, chromatin boundaries, and essential transport-dependent regulatory circuits. This review outlines new mechanistic links between nucleoporin function and cancer pathogenesis.Molecular cell 04/2010; 38(1):6-15. DOI:10.1016/j.molcel.2010.01.040 · 14.46 Impact Factor