CKAP4 inhibited growth and metastasis of hepatocellular carcinoma through regulating EGFR signaling

Li, Shuangxi; Liu, Lijuan; Dong, Lixue; Shi, Hanyu; Tan, Ye-Xiong; Zhang, Jiän; Zhang, Bo; Ding, Zhiwen; Jiang, Tianyi; Hu, He-Ping; Wang, Hongyang

doi:10.1007/s13277-014-2000-3

Cited by 20 publications

(28 citation statements)

References 25 publications

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“…5E and F). Overexpression of CKAP4 increased E-cadherin expression, which is consistent with previous report [22]. MYCT1 overexpression abolished the CKAP4-mediated E-cadherin up-regulation ( Fig.…”

Section: Ckap4 Interacts With Myct1supporting

confidence: 93%

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Transmembrane domain is crucial to the subcellular localization and function of Myc target 1

Gui

Yin

et al. 2015

J Cellular Molecular Medi

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Deregulation of c‐MYC occurs in a variety of human cancers. Overexpression of c‐MYC promotes cell growth, proliferation, apoptosis, transformation and genomic instability. MYC target 1 (MYCT1) is a direct target gene of c‐MYC, and its murine homologue MT‐MC1 recapitulated multiple c‐Myc‐related phenotypes. However, the molecular mechanism of MYCT1 remains unclear. Here, we identified the transmembrane (TM) domain of MYCT1, not the nuclear localization sequence, is indispensable to the vesicle‐associated localization of MYCT1 protein in the cytoplasmic membrane vesicle. Overexpression of MYCT1, not MYCT1 (ΔTM), decreased cell viability under serum deprivation and increased tumour cell migration ability. We further identified CKAP4 interacted with MYCT1 and contributed to the function of MYCT1. In addition, we found that a mutation, A88D, which is observed in patient sample, changed the localization, and abolished the effect on cell viability and cell migration, suggesting that the TM domain is critical to MYCT1.

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Section: Ckap4 Interacts With Myct1supporting

confidence: 93%

“…It was reported that CKAP4 plays important roles in several cellular processes, including endoplasmic reticulum anchoring 18 and morphology determination 19, regulation of Dicer function 20, cell proliferation 21 and tumour migration 22, 23. Knockdown of CKAP4 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Transmembrane domain is crucial to the subcellular localization and function of Myc target 1

Gui

Yin

et al. 2015

J Cellular Molecular Medi

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“…APF inhibits Akt activity and proliferation in bladder cells through CKAP4 (Shahjee et al, ). In HCC cells, CKAP4 associates with EGF receptors and inhibits EGFR signalling, resulting in decreased proliferation and invasion capabilities (Li et al, ). It is unknown whether other CKAP4 ligands, such as SP‐A and tPA, are involved in the proliferation of these cancer cells.…”

Section: Dkk1 and Ckap4 Are Required For Cancer Cell Proliferationmentioning

confidence: 99%

The Dickkopf1‐cytoskeleton‐associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy

Kikuchi

Fumoto

Kimura

2017

British J Pharmacology

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Dickkopf 1 (DKK1) is a secreted protein and antagonizes oncogenic Wnt signalling by binding to the Wnt co-receptor, low-density lipoprotein receptor-related protein 6. DKK1 has also been suggested to regulate its own signalling, associated with tumour aggressiveness. However, the underlying mechanism by which DKK1 promotes cancer cell proliferation has remained to be clarified for a long time. The cytoskeleton-associated protein 4 (CKAP4), originally identified as an endoplasmic reticulum membrane protein, was recently found to act as a novel DKK1 receptor. DKK1 stimulates cancer cell proliferation when CKAP4 is expressed on the cell surface membrane. Although there are no tyrosine residues in the intracellular region of CKAP4, CKAP4 forms a complex with PI3K upon the binding of DKK1, leading to the activation of Akt. Both DKK1 and CKAP4 are frequently expressed in pancreatic and lung tumours, and their simultaneous expression is negatively correlated with prognosis. Knockdown of CKAP4 in cancer cells and treatment of mice with the anti-CKAP4 antibody inhibit Akt activity in cancer cells and suppress xenograft tumour formation, suggesting that CKAP4 may represent a therapeutic target for cancers expressing both DKK1 and CKAP4. This review will provide details of the novel DKK1-CKAP4 signalling axis that promotes cancer proliferation and discuss the possibility of targeting this pathway in future cancer drug development.

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“…As mentioned, a population of CLIMP-63 was reported to act as a cell-surface signaling receptor, indicative of its presence at the plasma membrane (18)(19)(20)(21)37). We investigated whether ZDHHC6 affects the abundance of CLIMP-63 at the plasma membrane using a surface biotinylation assay, wherein all surface proteins were chemically modified, isolated with streptavidin beads, and CLIMP-63 was subsequently identified by western blot.…”

Section: Climp-63 Is a Substrate For Zdhhc6 Which Regulates Its Plasmentioning

confidence: 99%

“…between two CLIMP-63 molecules present in opposing membrane patches "across" the ER lumen (6). CLIMP-63 has also been reported to be present at the plasma membrane, acting as a receptor for various ligands in a tissue-dependent manner (18)(19)(20)(21). How these different roles relate to each other, however, and how they are controlled is unknown.…”

Section: Introductionmentioning

confidence: 99%

The architecture of the endoplasmic reticulum is regulated by the reversible lipid modification of the shaping protein CLIMP-63

Sandoz

Abrami

et al. 2018

Preprint

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The endoplasmic reticulum (ER) has a complex morphology generated and maintained by membrane-shaping proteins and membrane energy minimization, though not much is known about how it is regulated. The architecture of this intracellular organelle is balanced between large, thin sheets that are densely packed in the perinuclear region and a connected network of branched, elongated tubules that extend throughout the cytoplasm. Sheet formation is known to involve the cytoskeleton-linking membrane protein 63 (CLIMP-63), though its regulation and the depth of its involvement remain unknown. Here we show that the post-translational modification of CLIMP-63 by the palmitoyltransferase ZDHHC6 controls the relative distribution of CLIMP-63 between the ER and the plasma membrane. By combining data-driven mathematical modeling, predictions, and experimental validation, we found that the attachment of a medium chain fatty acid, so-called S-palmitoylation, to the unique CLIMP-63 cytoplasmic cysteine residue drastically reduces its turnover rate, and thereby controls its abundance. Light microscopy and focused ion beam electron microcopy further revealed that enhanced CLIMP-63 palmitoylation leads to strong ER-sheet proliferation. Altogether, we show that ZDHHC6-mediated Spalmitoylation regulates the cellular localization of CLIMP-63, the morphology of the ER, and the interconversion of ER structural elements in mammalian cells through its action on the CLIMP-63 protein.Eukaryotic cells subcompartmentalize their various functions into organelles, the shape of each being specific and necessary for its proper role. However, how these shapes are generated and controlled is poorly understood. The endoplasmic reticulum is the largest membrane-bound intracellular compartment, accounting for more than 50% of all cellular membranes. We found that the shape and quantity of its sheet-like structures are controlled by a specific protein, cytoskeleton-linking membrane protein 63, through the acquisition of a lipid chain attached by an enzyme called ZDHHC6. Thus, by modifying the ZDHHC6 amounts, a cell can control the shape of its ER. The modeling and prediction technique used herein also provides a method for studying the interconnected function of other post-translational modifications in organelles.

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CKAP4 inhibited growth and metastasis of hepatocellular carcinoma through regulating EGFR signaling

Cited by 20 publications

References 25 publications

Transmembrane domain is crucial to the subcellular localization and function of Myc target 1

Transmembrane domain is crucial to the subcellular localization and function of Myc target 1

The Dickkopf1‐cytoskeleton‐associated protein 4 axis creates a novel signalling pathway and may represent a molecular target for cancer therapy

The architecture of the endoplasmic reticulum is regulated by the reversible lipid modification of the shaping protein CLIMP-63

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