Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

Pal, Kuntal; Bandyopadhyay, Abhishek; Zhou, Xuemei; Xu, Qingping; Marciano, David; Brunzelle, J.S.; Yerrum, Smitha; Griffin, Patrick R.; Woude, George Vande; Melcher, Karsten; Xu, Hongjiao

doi:10.1016/j.str.2017.04.015

Cited by 21 publications

(14 citation statements)

References 51 publications

(53 reference statements)

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“…For example, in the Tpr-MET kinase fusion, residues 2–142 of Tpr replace the regulatory domains of the MET kinase to yield a constitutively active kinase (277). This isolated fragment of Tpr homodimerizes and further oligomerizes, and although these oligomerization states may not occur in the context of the full-length protein and within the NPC, they are certainly important for oncogenic MET activation (278). In this example, fusion with a nucleoporin seems to be coincidental.…”

Section: Nucleoporin Structure and Diseasementioning

confidence: 99%

The Structure of the Nuclear Pore Complex (An Update)

Lin

Hoelz

2019

Annu. Rev. Biochem.

359

440

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The nuclear pore complex (NPC) serves as the sole bidirectional gateway of macromolecules in and out of the nucleus. Owing to its size and complexity (~1,000 protein subunits, ~110 MDa in humans), the NPC has remained one of the foremost challenges for structure determination. Structural studies have now provided atomic-resolution crystal structures of most nucleoporins. The acquisition of these structures, combined with biochemical reconstitution experiments, cross-linking mass spectrometry, and cryo–electron tomography, has facilitated the determination of the near-atomic overall architecture of the symmetric core of the human, fungal, and algal NPCs. Here, we discuss the insights gained from these new advances and outstanding issues regarding NPC structure and function. The powerful combination of bottom-up and top-down approaches toward determining the structure of the NPC offers a paradigm for uncovering the architectures of other complex biological machines to near-atomic resolution.

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Section: Nucleoporin Structure and Diseasementioning

confidence: 99%

The Structure of the Nuclear Pore Complex (An Update)

Lin

Hoelz

2019

Annu. Rev. Biochem.

359

440

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“…HOOK3 protein contains one calponin-homology domain and two cytosolic coiled-coil domains. Some researchers have proposed that partner-enforced dimerization of FGFR1 is essential for EMS pathogenesis, and that the coiled-coil domain induces dimerization and activation of fusion kinases [ 28 , 52 ]. The chimeric HOOK3-FGFR1 fusion protein contains the coiled-coil domain from HOOK3, indicating its potential leukemogenesis role in EMS.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel HOOK3-FGFR1 fusion gene involved in activation of the NF-kappaB pathway

et al. 2022

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Background Rearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene result in 8p11 myeloproliferative syndrome (EMS), which is a rare and aggressive hematological malignancy that is often initially diagnosed as myelodysplastic syndrome (MDS). Clinical outcomes are typically poor due to relative resistance to tyrosine kinase inhibitors (TKIs) and rapid transformation to acute leukemia. Deciphering the transcriptomic signature of FGFR1 fusions may open new treatment strategies for FGFR1 rearrangement patients. Methods DNA sequencing (DNA-seq) was performed for 20 MDS patients and whole exome sequencing (WES) was performed for one HOOK3-FGFR1 fusion positive patient. RNA sequencing (RNA-seq) was performed for 20 MDS patients and 8 healthy donors. Fusion genes were detected using the STAR-Fusion tool. Fluorescence in situ hybridization (FISH), quantitative real-time PCR (qRT-PCR), and Sanger sequencing were used to confirm the HOOK3-FGFR1 fusion gene. The phosphorylation antibody array was performed to validate the activation of nuclear factor-kappaB (NF-kappaB) signaling. Results We identified frequently recurrent mutations of ASXL1 and U2AF1 in the MDS cohort, which is consistent with previous reports. We also identified a novel in-frame HOOK3-FGFR1 fusion gene in one MDS case with abnormal monoclonal B-cell lymphocytosis and ring chromosome 8. FISH analysis detected the FGFR1 break-apart signal in myeloid blasts only. qRT-PCR and Sanger sequencing confirmed the HOOK3-FGFR1 fusion transcript with breakpoints located at the 11th exon of HOOK3 and 10th exon of FGFR1, and Western blot detected the chimeric HOOK3-FGFR1 fusion protein that is presumed to retain the entire tyrosine kinase domain of FGFR1. The transcriptional feature of HOOK3-FGFR1 fusion was characterized by the significant enrichment of the NF-kappaB pathway by comparing the expression profiling of FGFR1 fusion positive MDS with 8 healthy donors and FGFR1 fusion negative MDS patients. Further validation by phosphorylation antibody array also showed NF-kappaB activation, as evidenced by increased phosphorylation of p65 (Ser 536) and of IKBalpha (Ser 32). Conclusions The HOOK3-FGFR1 fusion gene may contribute to the pathogenesis of MDS and activate the NF-kappaB pathway. These findings highlight a potential novel approach for combination therapy for FGFR1 rearrangement patients.

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“…HOOK3 protein contains one calponin-homology domain and two cytosolic coiled-coil domains. Some researchers have proposed that partner-enforced dimerization of FGFR1 is essential for EMS pathogenesis, and that the coiled-coil domain induces dimerization and activation of fusion kinases [28,52]. The chimeric HOOK3-FGFR1 fusion protein contains the coiled-coil domain from HOOK3, indicating its potential leukemogenesis role in EMS.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel HOOK3-FGFR1 Fusion Gene Involved in Activation of The NF-kappaB Pathway

Zhang

Wang

Yan

et al. 2021

Preprint

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BackgroundRearrangements involving the fibroblast growth factor receptor 1 (FGFR1) gene result in 8p11 myeloproliferative syndrome (EMS), which is a rare and aggressive hematological malignancy that is often initially diagnosed as myelodysplastic syndrome (MDS). Clinical outcomes are typically poor due to relative resistance to tyrosine kinase inhibitors (TKIs) and rapid transformation to acute leukemia. Deciphering the transcriptomic signature of FGFR1 fusions may open new treatment strategies for FGFR1 rearrangement patients.MethodsDNA sequencing (DNA-seq) was performed for 20 MDS patients and whole exome sequencing (WES) was performed for one HOOK3-FGFR1 fusion positive patient. RNA sequencing (RNA-seq) was performed for 20 MDS patients and 8 healthy donors. Fusion genes were detected using the STAR-Fusion tool. Fluorescence in situ hybridization (FISH), quantitative real-time PCR (qRT-PCR), and Sanger sequencing were used to confirm the HOOK3-FGFR1 fusion gene. The phosphorylation antibody array was performed to validate the activation of nuclear factor-kappaB (NF-kappaB) signaling. ResultsWe identified frequently recurrent mutations of ASXL1 and U2AF1 in the MDS cohort, which is consistent with previous reports. We also identified a novel in-frame HOOK3-FGFR1 fusion gene in one MDS case with abnormal monoclonal B-cell lymphocytosis and ring chromosome 8. FISH analysis detected the FGFR1 break-apart signal in myeloid blasts only. qRT-PCR and Sanger sequencing confirmed the HOOK3-FGFR1 fusion transcript with breakpoints located at the 11th exon of HOOK3 and 10th exon of FGFR1, and Western blot detected the chimeric HOOK3-FGFR1 fusion protein that is presumed to retain the entire tyrosine kinase domain of FGFR1. The transcriptional feature of HOOK3-FGFR1 fusion was characterized by the significant enrichment of the NF-kappaB pathway by comparing the expression profiling of FGFR1 fusion positive MDS with 8 healthy donors and FGFR1 fusion negative MDS patients. Further validation by phosphorylation antibody array also showed NF-kappaB activation, as evidenced by increased phosphorylation of p65 (Ser 536) and of IKBalpha (Ser 32). ConclusionThe HOOK3-FGFR1 fusion gene may contribute to the pathogenesis of MDS and activate the NF-kappaB pathway. These findings highlight a potential novel approach for combination therapy for FGFR1 rearrangement patients.

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Structural Basis of TPR-Mediated Oligomerization and Activation of Oncogenic Fusion Kinases

Cited by 21 publications

References 51 publications

The Structure of the Nuclear Pore Complex (An Update)

The Structure of the Nuclear Pore Complex (An Update)

Identification of a novel HOOK3-FGFR1 fusion gene involved in activation of the NF-kappaB pathway

Identification of a Novel HOOK3-FGFR1 Fusion Gene Involved in Activation of The NF-kappaB Pathway

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