La FAM fatale: USP9X in development and disease

Cellular and Molecular Life Sciences, Год журнала: 2015, Номер 72(11), С. 2075 - 2089

Опубликована: Фев. 11, 2015

Deubiquitylating enzymes (DUBs), act downstream of ubiquitylation. As such, these post-post-translational modifiers function as the final arbitrators a protein substrate's ubiquitylation status, thus regulating its fate. In most instances, DUBs moderate absolute level substrate, locality or activity, rather than being an "all-or-none" phenomenon. Yet, disruption this quantitative regulation can produce dramatic qualitative differences. The ubiquitin-specific protease 9X (USP9X/FAM) is substrate-specific DUB, which displays extraordinarily high sequence conservation from Drosophila to mammals. It primarily recent revelations USP9X's pivotal role in human cancers, both oncogene tumour suppressor, developmental disorders including intellectual disability, epilepsy, autism and delay that has led subsequent re-examination molecular cellular functions. Results experimental animal models have implicated USP9X neurodegeneration, Parkinson's Alzheimer's disease, well autoimmune diseases. review, we describe current accumulated knowledge on molecular, aspects within context biological consequences during normal development disease.

Язык: Английский

---

Loss of dual leucine zipper kinase signaling is protective in animal models of neurodegenerative disease

Science Translational Medicine, Год журнала: 2017, Номер 9(403)

Опубликована: Авг. 16, 2017

Blocking dual leucine zipper kinase slows disease progression in animal models of ALS and Alzheimer’s disease.

Язык: Английский

---

Diverse cellular and molecular modes of axon degeneration

Trends in Cell Biology, Год журнала: 2014, Номер 24(9), С. 515 - 523

Опубликована: Апрель 27, 2014

Язык: Английский

---

Activating Injury-Responsive Genes with Hypoxia Enhances Axon Regeneration through Neuronal HIF-1α

Neuron, Год журнала: 2015, Номер 88(4), С. 720 - 734

Опубликована: Ноя. 1, 2015

Язык: Английский

---

Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury

Neurobiology of Disease, Год журнала: 2015, Номер 77, С. 13 - 25

Опубликована: Фев. 26, 2015

Язык: Английский

---

Axon Degeneration Gated by Retrograde Activation of Somatic Pro-apoptotic Signaling

Cell, Год журнала: 2016, Номер 164(5), С. 1031 - 1045

Опубликована: Фев. 1, 2016

During development, sensory axons compete for limiting neurotrophic support, and local neurotrophin insufficiency triggers caspase-dependent axon degeneration. The signaling driving degeneration upon deprivation is proposed to reside within axons. Our results instead support a model in which, despite the apoptotic machinery being present axons, cell body an active participant gating axonal caspase activation Loss of trophic initiates retrograde somatic pro-apoptotic pathway, turn, required distal via anterograde pro-degenerative factor. At molecular level, convergence point two pathways whose integrated action drives upregulation Puma, unexpectedly, confined body. Puma then overcomes inhibition by pro-survival Bcl-xL Bcl-w program, highlighting role as arbiter large-scale removal.

Язык: Английский

---

Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling

Proceedings of the National Academy of Sciences, Год журнала: 2015, Номер 113(3), С. 763 - 768

Опубликована: Дек. 30, 2015

Significance Dual leucine-zipper kinase (DLK) is essential for responses to nerve injury and subsequent neural regeneration by controlling transfer of signals from damaged distal axons neuronal cell bodies. However, DLK predicted be freely diffusible, raising the question how it conveys long-distance, directional signals. Here we report that direct modification with lipid palmitate, a process called palmitoylation, critical retrograde signaling. At molecular level, palmitoylation targets trafficking vesicles, assembles DLK-dependent signaling complexes, also activity. This “multifunctional” explains mediates may previously unappreciated mechanism ensures specificity enzymatic in diverse types.

Язык: Английский

---

Signaling regulations of neuronal regenerative ability

Current Opinion in Neurobiology, Год журнала: 2014, Номер 27, С. 135 - 142

Опубликована: Апрель 12, 2014

Язык: Английский

---

The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: Alliance or contradiction? (Review)

International Journal of Oncology, Год журнала: 2015, Номер 47(2), С. 429 - 436

Опубликована: Июнь 16, 2015

The phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway and c-Jun N-terminal kinase (JNK) are responsible for regulating a variety of cellular processes including cell growth, migration, invasion apoptosis. These two pathways essential to the development progression tumors. dual roles JNK in apoptosis tumor determine different interactions between PI3K/Akt pathways. Activation can inhibit stress- cytokine-induced activation through Akt antagonizing formation JIP1-JNK module, as well activities upstream kinases ASK1, MKK4/7 MLK. On other hand, hyperactivation is also found cancers that harbor EGFR overexpression or loss PTEN. Understanding mechanism pathways, interplays these cancer may contribute identification novel therapeutic targets. In present report, we summarized current understanding networks, their biological cancers. addition, regulatory network were discussed.

Язык: Английский

---

KLF9 and JNK3 Interact to Suppress Axon Regeneration in the Adult CNS

Journal of Neuroscience, Год журнала: 2017, Номер 37(40), С. 9632 - 9644

Опубликована: Сен. 4, 2017

Neurons in the adult mammalian CNS decrease intrinsic axon growth capacity during development concert with changes Krüppel-like transcription factors (KLFs). KLFs regulate neurons including retinal ganglion cells (RGCs). Here, we found that knock-down of KLF9, an suppressor is normally upregulated 250-fold RGC development, promotes long-distance optic nerve regeneration rats both sexes. We identified a novel binding partner, MAPK10/JNK3 kinase, and JNK3 (c-Jun N-terminal kinase 3) critical for KLF9's axon-growth-suppressive activity. Interfering JNK3-binding domain or mutating two newly discovered serine phosphorylation acceptor sites, Ser106 Ser110, effectively abolished neurite suppression vitro promoted vivo . These findings demonstrate novel, physiologic role interaction KLF9 regenerative failure suggest new therapeutic strategies to promote CNS. SIGNIFICANCE STATEMENT Injured nerves fail regenerate spontaneously. Promoting has been major challenge field. knocking down factor 9 (KLF9) via shRNA after injury uncover important KLF9–JNK3 contributes studies potential approaches other degenerative diseases

Язык: Английский

---