Mitotic HOOK3 phosphorylation by ERK1c drives microtubule-dependent Golgi destabilization and fragmentation

Wortzel, Inbal; Maik-Rachline, Galia; Yadav, Sher Singh; Hanoch, Tamar; Seger, Rony

doi:10.1016/j.isci.2021.102670

Cited by 9 publications

(6 citation statements)

References 75 publications

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“…S5), even though they disrupt dynein’s interphase functions. Phosphorylation of the adaptors themselves could potentially play a part in cell cycle control as well, since mitotic phosphorylation sites have been identified in, or close to, LIC binding domains in Hooks 1-3, BICD2 and FIP3 (Collins et al, 2012; Dephoure et al, 2008; Olsen et al, 2010; Wortzel et al, 2021). We can speculate that KASH5-LIC interactions, while vital in the prolonged prophase of meiosis I, would not be required, or could be detrimental, once cells enter pro-metaphase and throughout meiosis II.…”

Section: Discussionmentioning

confidence: 99%

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein

Garner

Salter

Lau

et al. 2022

Preprint

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Cytoplasmic dynein-driven movement of chromosomes during prophase I of meiosis is essential for synapsis and genetic exchange. Dynein connects to chromosome telomeres via KASH5 and SUN1/2, which span the outer and inner nuclear envelopes, respectively. Here, we show that KASH5 promotes dynein motility in vitro, and cytosolic KASH5 inhibits dynein’s interphase functions. KASH5 interacts with either dynein light intermediate chain (DYNC1LI1 or DYNC1LI2) via a conserved linker-helix in the LIC C-terminal, and this region is also needed for dynein’s recruitment to other cellular membranes. KASH5’s N-terminal EF-hands are essential, as the interaction with dynein is disrupted by mutation of key calcium-binding residues, although it is not regulated by cellular calcium levels. Dynein can be recruited to KASH5 at the nuclear envelope independently of dynactin, while LIS1 is essential for dynactin incorporation into the KASH5-dynein complex. Altogether, we show that the trans-membrane protein KASH5 is an activating adaptor for dynein, and shed light on the hierarchy of assembly of KASH5-dynein-dynactin complexes.

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Section: Discussionmentioning

confidence: 99%

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein

Garner

Salter

Lau

et al. 2022

Preprint

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“…In addition, it was also shown that it translocates to the Golgi, where it regulates Golgi fragmentation during mitosis (Shaul & Seger, 2006; Wortzel et al, 2015). This effect is regulated by phosphorylating protein HOOK3 and possibly other Golgi proteins (Wortzel et al, 2021). These data indicate that alternatively spliced isoforms may significantly extend the specificity of the ERK cascade, but this may be different in distinct organisms.…”

Section: Discussionmentioning

confidence: 99%

ERK1b, a 46‐kDa ERK isoform that is differentially regulated by MEK

Yung

Yao

Hanoch

et al. 2022

Cell Biology International

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The extracellular signal-regulated kinases (ERK) 1 and 2 (ERK1/2) are members of the mitogen-activated protein kinase family. Using various stimulated rodent cells and kinase activation techniques, we identified a 46-kDa ERK. The kinetics of activation of this ERK isoform was similar to that of ERK1 and ERK2 under most but not all circumstances. We purified this isoform from rat cells followed by its cloning.The sequence of this isoform revealed that it is an alternatively spliced version of the 44-kDa ERK1 and therefore we termed it ERK1b. Interestingly, this isoform had a 26-amino acid insertion between residues 340 and 341 of ERK1, which results from Intron 7 insertion to the sequence. Examining the expression pattern, we found that ERK1b is detected mainly in rat and particularly in Ras-transformed Rat1 cells. In this cell line, ERK1b was more sensitive to extracellular stimulation than ERK1 and ERK2.Moreover, unlike ERK1 and ERK2, ERK1b had a very low binding affinity to MEK1. This low interaction led to nuclear localization of this isoform when expressed together with MEK1 under conditions in which ERK1 and ERK2 are retained in the cytoplasm. In addition, ERK1b was not coimmunoprecipitated with MEK1.We identified a new, 46-kDa ERK alternatively spliced isoform. Our results indicate that this isoform is the major one to respond to exogenous stimulation in Ras-transformed cells, probably due to its differential regulation by MAPK/ERK kinase and by phosphatases.

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“…HAUS augmin-like complex subunit 2 ( HAUS2 ) interacts with the γ-tubulin ring complex and is involved in spindle assembly ( Lawo et al, 2009 ), and one of its paralogs are associated with glioblastoma ( Ding et al, 2017 ). The hook microtubule tethering protein 3 ( HOOK3 ) gene is involved in protein binding and microtubule binding ( Kendrick et al, 2019 ; Wortzel et al, 2021 ). Its role has been implicated in neurological diseases such as Alzheimer’s disease ( Herrmann et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Brain Epitranscriptomic Analysis Revealed Altered A-to-I RNA Editing in Septic Patients

et al. 2022

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Recent studies suggest that RNA editing is associated with impaired brain function and neurological and psychiatric disorders. However, the role of A-to-I RNA editing during sepsis-associated encephalopathy (SAE) remains unclear. In this study, we analyzed adenosine-to-inosine (A-to-I) RNA editing in postmortem brain tissues from septic patients and controls. A total of 3024 high-confidence A-to-I RNA editing sites were identified. In sepsis, there were fewer A-to-I RNA editing genes and editing sites than in controls. Among all A-to-I RNA editing sites, 42 genes showed significantly differential RNA editing, with 23 downregulated and 19 upregulated in sepsis compared to controls. Notably, more than 50% of these genes were highly expressed in the brain and potentially related to neurological diseases. Notably, cis-regulatory analysis showed that the level of RNA editing in six differentially edited genes was significantly correlated with the gene expression, including HAUS augmin-like complex subunit 2 (HAUS2), protein phosphatase 3 catalytic subunit beta (PPP3CB), hook microtubule tethering protein 3 (HOOK3), CUB and Sushi multiple domains 1 (CSMD1), methyltransferase-like 7A (METTL7A), and kinesin light chain 2 (KLC2). Furthermore, enrichment analysis showed that fewer gene functions and KEGG pathways were enriched by edited genes in sepsis compared to controls. These results revealed alteration of A-to-I RNA editing in the human brain associated with sepsis, thus providing an important basis for understanding its role in neuropathology in SAE.

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Mitotic HOOK3 phosphorylation by ERK1c drives microtubule-dependent Golgi destabilization and fragmentation

Cited by 9 publications

References 75 publications

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein

The meiotic LINC complex component KASH5 is an activating adaptor for cytoplasmic dynein

ERK1b, a 46‐kDa ERK isoform that is differentially regulated by MEK

Brain Epitranscriptomic Analysis Revealed Altered A-to-I RNA Editing in Septic Patients

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