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1.
J Mol Cell Biol ; 12(6): 424-437, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31638145

RESUMO

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.


Assuntos
Membrana Celular/metabolismo , Movimento Celular , Quimiocinas CC/metabolismo , Proteínas do Citoesqueleto/metabolismo , Citoesqueleto/metabolismo , Acetilação , Actinas/metabolismo , Animais , Linhagem Celular Tumoral , Proteínas do Citoesqueleto/química , Células HEK293 , Humanos , Células LLC-PK1 , Fosfatidilinositol 4,5-Difosfato , Fosforilação , Conformação Proteica , Domínios Proteicos , Transporte Proteico , Especificidade por Substrato , Suínos , Fatores de Transcrição de p300-CBP/metabolismo
2.
J Mol Cell Biol ; 10(6): 527-538, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30016453

RESUMO

Heterochromatin protein 1α (HP1α) regulates chromatin specification and plasticity during cell fate decision. Different structural determinants account for HP1α localization and function during cell division cycle. Our earlier study showed that centromeric localization of HP1α depends on the epigenetic mark H3K9me3 in interphase, while its centromeric location in mitosis relies on uncharacterized PXVXL-containing factors. Here, we identified a PXVXL-containing protein, ligand-dependent nuclear receptor-interacting factor 1 (LRIF1), which recruits HP1α to the centromere of mitotic chromosomes and its interaction with HP1α is essential for accurate chromosome segregation during mitosis. LRIF1 interacts directly with HP1α chromoshadow domain via an evolutionarily conserved PXVXL motif within its C-terminus. Importantly, the LRIF1-HP1α interaction is critical for Aurora B activity in the inner centromere. Mutation of PXVXL motif of LRIF1 leads to defects in HP1α centromere targeting and aberrant chromosome segregation. These findings reveal a previously unrecognized direct link between LRIF1 and HP1α in centromere plasticity control and illustrate the critical role of LRIF1-HP1α interaction in orchestrating accurate cell division.


Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona/metabolismo , Segregação de Cromossomos , Mitose , Proteínas de Ligação a Telômeros/metabolismo , Proteínas de Ciclo Celular/genética , Linhagem Celular , Centrômero/metabolismo , Centrômero/ultraestrutura , Homólogo 5 da Proteína Cromobox , Células HeLa , Humanos , Mapas de Interação de Proteínas
3.
J Mol Cell Biol ; 8(2): 144-56, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26711306

RESUMO

Endoplasmic reticulum (ER) stress is involved in ischemic preconditioning that protects various organs from ischemia/reperfusion (I/R) injury. We established an in vivo ER stress preconditioning model in which tunicamycin was injected into rats before hepatic I/R. The hepatic I/R injury, demonstrated by serum aminotransferase level and the ultra-structure of the liver, was alleviated by administration of tunicamycin, which induced ER stress in rat liver by activating inositol-requiring enzyme 1 (IRE1) and upregulating 78 kDa glucose-regulated protein (GRP78). The proteomic identification for IRE1 binders revealed interaction and cooperation among receptor for activated C kinase 1 (RACK1), phosphorylated AMPK, and IRE1 under ER stress conditions in a spatiotemporal manner. Furthermore, in vitro ER stress preconditioning was induced by thapsigargin and tunicamycin in L02 and HepG2 cells. Surprisingly, BCL2 was found to be phosphorylated by IRE1 under ER stress conditions to prevent apoptotic process by activation of autophagy. In conclusion, ER stress preconditioning protects against hepatic I/R injury, which is orchestrated by IRE1-RACK1 axis through the activation of BCL2. Our findings provide novel insights into the molecular pathways underlying ER stress preconditioning-elicited cytoprotective effect against hepatic I/R injury.


Assuntos
Citoproteção , Estresse do Retículo Endoplasmático , Fígado/metabolismo , Fígado/patologia , Proteínas de Membrana/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Receptores de Superfície Celular/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Adenilato Quinase/metabolismo , Animais , Autofagia/efeitos dos fármacos , Proteína Beclina-1/metabolismo , Citoproteção/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado/ultraestrutura , Masculino , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos Sprague-Dawley , Receptores de Quinase C Ativada , Transdução de Sinais/efeitos dos fármacos , Tunicamicina/farmacologia
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