| 1. |
- Mazot, P, et al.
(författare)
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The constitutive activity of the ALK mutated at positions F1174 or R1275 impairs receptor trafficking
- 2011
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 30, s. 2017-2025
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Tidskriftsartikel (refereegranskat)abstract
- Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK), which is transiently expressed during development of the central and peripheral nervous system. ALK has been recently identified as a major neuroblastoma predisposition gene and activating mutations have also been identified in a subset of sporadic neuroblastoma tumors. Two hot spots of ALK mutations have been observed at positions F1174 and R1275. Here, we studied stably transfected cell lines expressing wild-type or F1174L- or R1275Q-mutated ALK in parallel with a neuroblastoma cell line (CLB-GE) in which the allele mutated at position F1174 is amplified. We observed that the mutated ALK variants were essentially intracellular and were largely retained in the reticulum/Golgi compartments. This localization was corroborated by a defect of N-linked glycosylation. Although the mutated receptors exhibited a constitutive activation, the minor pool of receptor addressed to the plasma membrane was much more tyrosine phosphorylated than the intracellular pool. The use of antagonist monoclonal antibodies suggested that the constitutive activity of the mutated receptors did not require the dimerization of the receptor, whereas adequate dimerization triggered by agonist monoclonal antibodies increased this activity. Finally, kinase inactivation of the mutated receptors restored maturation and cell-surface localization. Our results show that constitutive activation of ALK results in its impaired maturation and intracellular retention. Furthermore, they provide a rationale for the potential use of kinase inhibitors and antibodies in ALK-dependent tumors.Oncogene advance online publication, 17 January 2011; doi:10.1038/onc.2010.595.
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| 2. |
- Nilforoushan, Faramarz, et al.
(författare)
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GPS network monitors the Arabia-Eurasia collision deformation in Iran
- 2003
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Ingår i: Journal of Geodesy. - : Springer Science and Business Media LLC. - 0949-7714 .- 1432-1394. ; 77, s. 411-422
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Tidskriftsartikel (refereegranskat)abstract
- The rate of crustal deformation in Iran due to the Arabia–Eurasia collision is estimated. The results are based on new global positioning system (GPS) data. In order to address the problem of the distribution of the deformation in Iran, Iranian and French research organizations have carried out the first large-scale GPS survey of Iran. A GPS network of 28 sites (25 in Iran, two in Oman and one in Uzbekistan) has been installed and surveyed twice, in September 1999 and October 2001. Each site has been surveyed for a minimum observation of 4 days. GPS data processing has been done using the GAMIT-GLOBK software package. The solution displays horizontal repeatabilities of about 1.2 mm in 1999 and 2001. The resulting velocities allow us to constrain the kinematics of the Iranian tectonic blocks. These velocities are given in ITRF2000 and also relative to Eurasia. This last kinematic model demonstrates that (1) the north–south shortening from Arabia to Eurasia is 2–2.5 cm/year, less than previously estimated, and (2) the transition from subduction (Makran) to collision (Zagros) is very sharp and governs the different styles of deformation observed in Iran. In the eastern part of Iran, most of the shortening is accommodated in the Gulf of Oman, while in the western part the shortening is more distributed from south to north. The large faults surrounding the Lut block accommodate most of the subduction–collision transition.
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| 3. |
- Schönherr, Christina, et al.
(författare)
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Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells
- 2010
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Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 29:19, s. 2817-2830
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Tidskriftsartikel (refereegranskat)abstract
- Many different types of cancer originate from aberrant signaling from the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK), arising through different translocation events and overexpression. Further, activating point mutations in the ALK domain have been recently reported in neuroblastoma. To characterize signaling in the context of the full-length receptor, we have examined whether ALK is able to activate Rap1 and contribute to differentiation/proliferation processes. We show that ALK activates Rap1 via the Rap1-specific guanine-nucleotide exchange factor C3G, which binds in a constitutive complex with CrkL to activated ALK. The activation of the C3G/Rap1 pathway results in neurite outgrowth of PC12 cells, which is inhibited by either overexpression of Rap1GAP or siRNA-mediated knockdown of Rap1 itself or the guanine nucleotide exchange factor C3G. Significantly, this pathway also appears to function in the regulation of proliferation of neuroblastoma cells such as SK-N-SH and SH-SY5Y, because abrogation of Rap1 activity by Rap1-specific siRNA or overexpression of Rap1GAP reduces cellular growth. These results suggest that ALK activation of Rap1 may contribute to cell proliferation and oncogenesis of neuroblastoma driven by gain-of-function mutant ALK receptors.
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| 4. |
- Siaw, Joachim T., et al.
(författare)
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Loss of RET Promotes Mesenchymal Identity in Neuroblastoma Cells
- 2021
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary The anaplastic lymphoma kinase (ALK) and rearranged during transfection (RET) receptor tyrosine kinases (RTKs) are expressed in both the developing neural crest and the pediatric cancer neuroblastoma. Moreover, ALK is mutated in approximately 10% of neuroblastomas. Here, we investigated ALK and RET in neuroblastoma, with the aim of better understanding their respective contributions. Using neuroblastoma cell lines, we show that ALK modulates RET signaling at the level of RET phosphorylation, as well as at the level of transcription. Using CRISPR/Cas9, we generated RET knockout neuroblastoma cell lines and performed a multi-omics approach, combining RNA-Seq and proteomics to characterize the effect of deleting RET in a neuroblastoma context. Remarkably, we could show that loss of RET results in a striking epithelial-to-mesenchymal transition (EMT) phenotype, and we provide evidence that RET activity suppresses the mesenchymal phenotype in neuroblastoma. Aberrant activation of anaplastic lymphoma kinase (ALK) drives neuroblastoma (NB). Previous work identified the RET receptor tyrosine kinase (RTK) as a downstream target of ALK activity in NB models. We show here that ALK activation in response to ALKAL2 ligand results in the rapid phosphorylation of RET in NB cells, providing additional insight into the contribution of RET to the ALK-driven gene signature in NB. To further address the role of RET in NB, RET knockout (KO) SK-N-AS cells were generated by CRISPR/Cas9 genome engineering. Gene expression analysis of RET KO NB cells identified a reprogramming of NB cells to a mesenchymal (MES) phenotype that was characterized by increased migration and upregulation of the AXL and MNNG HOS transforming gene (MET) RTKs, as well as integrins and extracellular matrix components. Strikingly, the upregulation of AXL in the absence of RET reflects the development timeline observed in the neural crest as progenitor cells undergo differentiation during embryonic development. Together, these findings suggest that a MES phenotype is promoted in mesenchymal NB cells in the absence of RET, reflective of a less differentiated developmental status.
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| 5. |
- Vernant, P, et al.
(författare)
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Present-day crustal deformation and plate kinematics in the Middle East constrained by GPS measurements in Iran and northern Oman
- 2004
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Ingår i: Geophysical Journal International. - 0956-540X .- 1365-246X. ; 157:1, s. 381-398
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Tidskriftsartikel (refereegranskat)abstract
- A network of 27 GPS sites was implemented in Iran and northern Oman to measure displacements in this part of the Alpine–Himalayan mountain belt. We present and interpret the results of two surveys performed in 1999 September and 2001 October. GPS sites in Oman show northward motion of the Arabian Plate relative to Eurasia slower than the NUVEL-1A estimates (e.g. 22 ± 2 mm yr−1 at N8°± 5°E instead of 30.5 mm yr−1 at N6°E at Bahrain longitude). We define a GPS Arabia–Eurasia Euler vector of 27.9°± 0.5°N, 19.5°± 1.4°E, 0.41°± 0.1° Myr−1. The Arabia–Eurasia convergence is accommodated differently in eastern and western Iran. East of 58°E, most of the shortening is accommodated by the Makran subduction zone (19.5 ± 2 mm yr−1) and less by the Kopet-Dag (6.5 ± 2 mm yr−1). West of 58°E, the deformation is distributed in separate fold and thrust belts. At the longitude of Tehran, the Zagros and the Alborz mountain ranges accommodate 6.5 ± 2 mm yr−1 and 8 ± 2 mm yr−1 respectively. The right-lateral displacement along the Main Recent Fault in the northern Zagros is about 3 ± 2 mm yr−1, smaller than what was generally expected. By contrast, large right-lateral displacement takes place in northwestern Iran (up to 8 ± mm yr−1). The Central Iranian Block is characterized by coherent plate motion (internal deformation <2 mm yr−1). Sites east of 61°E show very low displacements relative to Eurasia. The kinematic contrast between eastern and western Iran is accommodated by strike-slip motions along the Lut Block. To the south, the transition zone between Zagros and Makran is under transpression with right-lateral displacements of 11 ± 2 mm yr−1.
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