更新于：2024-11-01

ROCK1 x AURK

更新于：2024-11-01

基本信息

关联

项与 ROCK1 x AURK 相关的药物

RR-1752

靶点

AURK x ROCK1

作用机制

ROCK1抑制剂 [+1]

在研机构

Translational Drug Development LLC

原研机构

Translational Drug Development LLC

在研适应症

骨髓纤维化

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 ROCK1 x AURK 相关的临床结果

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100 项与 ROCK1 x AURK 相关的转化医学

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0 项与 ROCK1 x AURK 相关的专利（医药）

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项与 ROCK1 x AURK 相关的文献（医药）

2023-11-01·Molecular & Cellular Proteomics

Proteomic and Phosphoproteomic Reprogramming in Epithelial Ovarian Cancer Metastasis

Article

作者: Li, Shawn S C ; Heinemann, Ilka U ; Shepherd, Trevor G ; Kakadia, Jenica H ; Frederick, Mallory I ; Hovey, Owen F J

Epithelial ovarian cancer (EOC) is a high-risk cancer presenting with heterogeneous tumors. The high incidence of EOC metastasis from primary tumors to nearby tissues and organs is a major driver of EOC lethality. We used cellular models of spheroid formation and readherence to investigate cellular signaling dynamics in each step toward EOC metastasis. In our system, adherent cells model primary tumors, spheroid formation represents the initiation of metastatic spread, and readherent spheroid cells represent secondary tumors. Proteomic and phosphoproteomic analyses show that spheroid cells are hypoxic and show markers for cell cycle arrest. Aurora kinase B abundance and downstream substrate phosphorylation are significantly reduced in spheroids and readherent cells, explaining their cell cycle arrest phenotype. The proteome of readherent cells is most similar to spheroids, yet greater changes in the phosphoproteome show that spheroid cells stimulate Rho-associated kinase 1 (ROCK1)-mediated signaling, which controls cytoskeletal organization. In spheroids, we found significant phosphorylation of ROCK1 substrates that were reduced in both adherent and readherent cells. Application of the ROCK1-specific inhibitor Y-27632 to spheroids increased the rate of readherence and altered spheroid density. The data suggest ROCK1 inhibition increases EOC metastatic potential. We identified novel pathways controlled by Aurora kinase B and ROCK1 as major drivers of metastatic behavior in EOC cells. Our data show that phosphoproteomic reprogramming precedes proteomic changes that characterize spheroid readherence in EOC metastasis.

2020-08-25·Oncotarget

The NKL-code for innate lymphoid cells reveals deregulated expression of NKL homeobox genes HHEX and HLX in anaplastic large cell lymphoma (ALCL)

Article

作者: Drexler, Hans G. ; Meyer, Corinna ; Nagel, Stefan ; MacLeod, Roderick A.F. ; Kaufmann, Maren ; Pommerenke, Claudia

NKL homeobox genes encode developmental transcription factors and display an NKL-code according to their physiological expression pattern in hematopoiesis. Here, we analyzed public transcriptome data from primary innate lymphoid cells (ILCs) for NKL homeobox gene activities and found that ILC3 expressed exclusively HHEX while in ILC1 and ILC2 these genes were silenced. Deregulation of the NKL-code promotes hematopoietic malignancies, including anaplastic large cell lymphoma (ALCL) which reportedly may derive from ILC3. Accordingly, we analyzed NKL homeobox gene activities in ALCL cell lines and investigated their role in this malignancy. Transcriptome analyses demonstrated low expression levels of HHEX but powerfully activated HLX. Forced expression of HHEX in ALCL cell lines induced genes involved in apoptosis and ILC3 differentiation, indicating tumor suppressor activity. ALCL associated NPM1-ALK and JAK-STAT3-signalling drove enhanced expression of HLX while discounting HHEX. Genomic profiling revealed copy number gains at the loci of HLX and STAT3 in addition to genes encoding both STAT3 regulators (AURKA, BCL3, JAK3, KPNB1, NAMPT, NFAT5, PIM3, ROCK1, SIX1, TPX2, WWOX) and targets (BATF3, IRF4, miR135b, miR21, RORC). Transcriptome data of ALCL cell lines showed absence of STAT3 mutations while MGA was mutated and downregulated, encoding a novel potential STAT3 repressor. Furthermore, enhanced IL17F-signalling activated HLX while TGFbeta-signalling inhibited HHEX expression. Taken together, our data extend the scope of the NKL-code for ILCs and spotlight aberrant expression of NKL homeobox gene HLX in ALCL. HLX represents a direct target of ALCL hallmark factor STAT3 and deregulates cell survival and differentiation in this malignancy.

2019-11-01·Journal of Cell Science

Cell cycle-independent furrowing triggered by phosphomimetic mutations of the INCENP STD motif requires Plk1

Article

作者: Ruchaud, Sandrine ; Papini, Diana ; Fant, Xavier ; Desban, Nathalie ; Samejima, Kumiko ; Feizbakhsh, Omid ; Ogawa, Hiromi ; Askin, Bilge ; Earnshaw, William C ; Ly, Tony

ABSTRACTTimely and precise control of Aurora B kinase, the chromosomal passenger complex (CPC) catalytic subunit, is essential for accurate chromosome segregation and cytokinesis. Post-translational modifications of CPC subunits are directly involved in controlling Aurora B activity. Here, we identified a highly conserved acidic STD-rich motif of INCENP that is phosphorylated during mitosis in vivo and by Plk1 in vitro and is involved in controlling Aurora B activity. By using an INCENP conditional-knockout cell line, we show that impairing the phosphorylation status of this region disrupts chromosome congression and induces cytokinesis failure. In contrast, mimicking constitutive phosphorylation not only rescues cytokinesis but also induces ectopic furrows and contractile ring formation in a Plk1- and ROCK1-dependent manner independent of cell cycle and microtubule status. Our experiments identify the phospho-regulation of the INCENP STD motif as a novel mechanism that is key for chromosome alignment and cytokinesis.This article has an associated First Person interview with the first author of the paper.