Cytoskeleton-Associated Protein 4: Functions Beyond the Endoplasmic Reticulum in Physiology and Disease

Tuffy, Kevin M.; Planey, Sonia Lobo

doi:10.5402/2012/142313

Cited by 11 publications

(10 citation statements)

References 60 publications

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“…These data were further validated by quantitative real-time PCR (qRT–PCR) analysis of mRNA from KMS18 and KMS27 cells transfected with siRNA Deptor or siRNA negative control (Figure 3A and 3B ). Consistent with these results, western blot analysis from these cells revealed that Deptor depletion produced a significant reduction of ERLIN2, KEAP1, PSEN2 protein levels, with a concomitant increase of DERL3 amounts (Figure 3C ) [ 30 – 32 ]. In agreement, ectopic over-expression of Deptor in U266 cells, a MM cell line with low expression of this protein, produced an increase of ERLIN2, KEAP1 and CKAP4 protein levels with a concomitant decrease of DERL3 expression ( Supplementary Figure S1A ).…”

Section: Resultssupporting

confidence: 66%

Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells

Catena¹,

Bruno²,

Nicola³

et al. 2016

Oncotarget

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Multiple myeloma (MM) is a malignant disorder of plasma cells characterized by active production and secretion of monoclonal immunoglobulins (IgG), thus rendering cells prone to endoplasmic reticulum (ER) stress. For this reason, MM cell survival requires to maintain ER homeostasis at basal levels. Deptor is an mTOR binding protein, belonging to the mTORC1 and mTORC2 complexes. It was reported that Deptor is overexpressed in MM cells where it inhibits mTOR kinase activity and promotes cell survival by activating Akt signaling. Here we identify Deptor as a nuclear protein, able to bind DNA and regulate transcription in MM cells. In particular, we found that Deptor plays an important role in the maintenance of the ER network, sustaining the expression of several genes involved in this pathway. In agreement with this, Deptor depletion induces ER stress and synergizes the effect of the proteasome inhibitor bortezomib (Bz) in MM cells. These findings provide important new insights in the ER stress control in MM cells.

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Section: Resultssupporting

confidence: 66%

Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells

Catena¹,

Bruno²,

Nicola³

et al. 2016

Oncotarget

View full text Add to dashboard Cite

show abstract

“…As shown in Figure 1H, all maytansinoid-based ADCs, including T-DM1, α-CD22-DM1, α-CD79b-DM1, and α-gD-DM4, bound to CKAP5, whereas brentuximab vedotin, an auristatin (a potent antimiotic agent)-based ADC, trastuzumab, pertuzumab, and control IgG failed to bind CKAP5. Figure 1I showed that both CKAP4, a type II transmembrane protein [29], and CKAP2 were unable to bind to T-DM1.…”

Section: Resultsmentioning

confidence: 99%

Payload of T-DM1 binds to cell surface cytoskeleton-associated protein 5 to mediate cytotoxicity of hepatocytes

et al. 2018

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Off-target toxicity is a major cause of dose-limiting toxicity for antibody-drug conjugates (ADCs), mechanisms of which remain poorly understood. Here, we demonstrate that cytoskeleton-associated protein 5 (CKAP5) serves as a cell surface target for T-DM1 and that binding of T-DM1 to CKAP5 is mediated by payload (DM1). This study introduces a novel molecular mechanism of ADC payload-mediated interaction with cell surface molecules to induce cytotoxicity. Upon binding to CKAP5, T-DM1 causes cell membrane damage and leads to calcium influx into the cells, resulting in disorganized microtubule network and apoptosis. While binding of T-DM1 with HER2 is critical for killing HER2-positive tumor cells, our data suggest that cytotoxicity induced by T-DM1 interaction with CKAP5 may preferentially damage normal cells/tissues where HER2 expression is low or missing to cause off-target toxicity. This study provides molecular basis of ADC-induced off-target cytotoxicity and opens a new avenue for developing next generation of ADCs.

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“…Overexpression of CKAP4 reversed the miR-7-mediated effects on VSMCs. As the receptor of dickkopf-related protein 1 (DKK1), CKAP4 mediates downstream signaling to promote cellular proliferation and inhibit apoptosis through the activation of the PI3K/AKT pathway (27). Apoptosis of VSMCs is crucial for normal vascular remodeling (28).…”

Section: Discussionmentioning

confidence: 99%

CDR1as/miR‑7/CKAP4 axis contributes to the pathogenesis of abdominal aortic aneurysm by regulating the proliferation and apoptosis of primary vascular smooth muscle cells

2020

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Abdominal aortic aneurysm (AAA) is characterized as dilation of the aortic wall. Dysregulation of vascular smooth muscle cells (VSMCs) can contribute to the development of this phenotype. Circular RNAs and microRNAs (miRNAs) can regulate the proliferation and apoptosis of VSMCs. This present study aimed to identify the mechanisms of action behind the regulation of cerebellar degeneration-related protein 1 antisense RNA (CDR1as)/miRNA (miR)-7 in VSMCs. The expression levels of miR-7 were upregulated, whereas the levels of CDR1as and cytoskeleton-associated protein 4 (CKAP4) were downregulated in aortic specimens obtained from 10 patients who underwent surgery for AAA compared with aortic specimens from 10 control patients who underwent coronary artery bypass surgery. The molecular mechanism of action of CDR1as/miR-7 was investigated in primary VSMCs. The results of Cell Counting kit-8 and cell growth curve assays revealed that overexpression of CDR1as and knockdown of miR-7, increased VSMC proliferation, whereas knockdown of CDR1as and overexpression of miR-7 suppressed VSMC proliferation. In addition, overexpression of CDR1as and knockdown of miR-7, suppressed apoptosis in VSMCs, indicated by the decreased levels of reactive oxygen species (ROS) and lactate dehydrogenase (LDH) activity, whereas knockdown of CDR1as and overexpression of miR-7 exhibited the opposite effects. The results of luciferase reporter and biotin pull-down assays confirmed that CDR1as directly bound to miR-7 and suppressed its expression. Additionally, the CDR1as-induced proliferation and suppressed apoptosis was reversed by the overexpression of miR-7. Furthermore, luciferase reporter, reverse transcription-quantitative PCR and western blot assays revealed that miR-7 directly targeted CKAP4 and suppressed its expression. Additionally, the miR-7-suppressed proliferation and increased ROS and LDH activity were reversed by the overexpression of CKAP4. CDR1as also decreased caspase 3/7 activity, which was reversed by miR-7 mimics. miR-7 increased the activity of caspase 3/7, which was again reversed by the overexpression of CKAP4. Therefore, CDR1as, miR-7 and CKAP4 may act in the same pathway to regulate VSMC proliferation and apoptosis.

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Cytoskeleton-Associated Protein 4: Functions Beyond the Endoplasmic Reticulum in Physiology and Disease

Cited by 11 publications

References 60 publications

Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells

Deptor transcriptionally regulates endoplasmic reticulum homeostasis in multiple myeloma cells

Payload of T-DM1 binds to cell surface cytoskeleton-associated protein 5 to mediate cytotoxicity of hepatocytes

CDR1as/miR‑7/CKAP4 axis contributes to the pathogenesis of abdominal aortic aneurysm by regulating the proliferation and apoptosis of primary vascular smooth muscle cells

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