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  • 1
    In: Journal of Molecular Cell Biology, Oxford University Press (OUP), Vol. 13, No. 12 ( 2022-01-29), p. 841-852
    Abstract: Chromosome segregation in mitosis is orchestrated by the dynamic interactions between the kinetochore and spindle microtubules. Our recent studies show that mitotic motor CENP-E cooperates with SKAP and forms a link between kinetochore core MIS13 complex and spindle microtubule plus-ends to achieve accurate chromosome alignment in mitosis. However, it remains elusive how SKAP regulates kinetochore attachment from lateral association to end-on attachment during metaphase alignment. Here, we identify a novel interaction between Aurora B and SKAP that orchestrates accurate interaction between the kinetochore and dynamic spindle microtubules. Interestingly, SKAP spontaneously phase-separates in vitro via weak, multivalent interactions into droplets with fast internal dynamics. SKAP and Aurora B form heterogeneous coacervates in vitro, which recapitulate the dynamics and behavior of SKAP comets in vivo. Importantly, SKAP interaction with Aurora B via phase separation is essential for accurate chromosome segregation and alignment. Based on those findings, we reason that SKAP–Aurora B interaction via phase separation constitutes a dynamic pool of Aurora B activity during the lateral to end-on conversion of kinetochore–microtubule attachments to achieve faithful cell division.
    Type of Medium: Online Resource
    ISSN: 1759-4685
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 2500949-7
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  • 2
    In: Journal of Neuroimaging, Wiley, Vol. 33, No. 4 ( 2023-07), p. 625-631
    Abstract: Spontaneous intracranial hypotension (SIH) is a known cause of headaches and neurologic symptoms, but the frequency of cranial nerve symptoms and abnormalities on magnetic resonance imaging (MRI) has not been well described. The purpose of this study was to document cranial nerve findings in patients with SIH and determine the relationship between imaging findings and clinical symptoms. Methods Patients diagnosed with SIH with pre‐treatment brain MRI at a single institution from September 2014 to July 2017 were retrospectively reviewed to determine the frequency of clinically significant visual changes/diplopia (cranial nerves 3 and 6) and hearing changes/vertigo (cranial nerve 8). A blinded review of brain MRIs before and after treatment was conducted to assess for abnormal contrast enhancement of cranial nerves 3, 6, and 8. Imaging results were correlated with clinical symptoms. Results Thirty SIH patients with pre‐treatment brain MRI were identified. Sixty‐six percent of patients had vision changes, diplopia, hearing changes, and/or vertigo. Cranial nerve 3 and/or 6 enhancement was present in nine patients on MRI, with 7/9 patients experiencing visual changes and/or diplopia (odds ratio [OR] 14.9, 95% confidence interval [CI] 2.2‐100.8, p = .006). Cranial nerve 8 enhancement was present in 20 patients on MRI, with 13/20 patients experiencing hearing changes and/or vertigo (OR 16.7, 95% CI 1.7‐160.6, p = .015). Conclusions SIH patients with cranial nerve findings on MRI were more likely to have associated neurologic symptoms than those without imaging findings. Cranial nerve abnormalities on brain MRI should be reported in suspected SIH patients as they may support the diagnosis and explain patient symptoms.
    Type of Medium: Online Resource
    ISSN: 1051-2284 , 1552-6569
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2035400-9
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  • 3
    In: Journal of Molecular Cell Biology, Oxford University Press (OUP), Vol. 12, No. 7 ( 2020-09-16), p. 486-498
    Abstract: Error-free mitosis depends on accurate chromosome attachment to spindle microtubules, which is monitored by the spindle assembly checkpoint (SAC) signaling. As an upstream factor of SAC, the precise and dynamic kinetochore localization of Mps1 kinase is critical for initiating and silencing SAC signaling. However, the underlying molecular mechanism remains elusive. Here, we demonstrated that the multisite interactions between Mps1 and Ndc80 complex (Ndc80C) govern Mps1 kinetochore targeting. Importantly, we identified direct interaction between Mps1 tetratricopeptide repeat domain and Ndc80C. We further identified that Mps1 C-terminal fragment, which contains the protein kinase domain and C-tail, enhances Mps1 kinetochore localization. Mechanistically, Mps1 C-terminal fragment mediates its dimerization. Perturbation of C-tail attenuates the kinetochore targeting and activity of Mps1, leading to aberrant mitosis due to compromised SAC function. Taken together, our study highlights the importance of Mps1 dimerization and multisite interactions with Ndc80C in enabling responsive SAC signaling.
    Type of Medium: Online Resource
    ISSN: 1759-4685
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2500949-7
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  • 4
    In: Journal of Molecular Cell Biology, Oxford University Press (OUP), Vol. 12, No. 6 ( 2020-07-03), p. 424-437
    Abstract: Ezrin, a membrane–cytoskeleton linker protein, plays an essential role in cell polarity establishment, cell migration, and division. Recent studies show that ezrin phosphorylation regulates breast cancer metastasis by promoting cancer cell survivor and promotes intrahepatic metastasis via cell migration. However, it was less characterized whether there are additional post-translational modifications and/or post-translational crosstalks on ezrin underlying context-dependent breast cancer cell migration and invasion. Here we show that ezrin is acetylated by p300/CBP-associated factor (PCAF) in breast cancer cells in response to CCL18 stimulation. Ezrin physically interacts with PCAF and is a cognate substrate of PCAF. The acetylation site of ezrin was mapped by mass spectrometric analyses, and dynamic acetylation of ezrin is essential for CCL18-induced breast cancer cell migration and invasion. Mechanistically, the acetylation reduced the lipid-binding activity of ezrin to ensure a robust and dynamic cycling between the plasma membrane and cytosol in response to CCL18 stimulation. Biochemical analyses show that ezrin acetylation prevents the phosphorylation of Thr567. Using atomic force microscopic measurements, our study revealed that acetylation of ezrin induced its unfolding into a dominant structure, which prevents ezrin phosphorylation at Thr567. Thus, these results present a previously undefined mechanism by which CCL18-elicited crosstalks between the acetylation and phosphorylation on ezrin control breast cancer cell migration and invasion. This suggests that targeting PCAF signaling could be a potential therapeutic strategy for combating hyperactive ezrin-driven cancer progression.
    Type of Medium: Online Resource
    ISSN: 1759-4685
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2020
    detail.hit.zdb_id: 2500949-7
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