更新于：2024-11-01

MAP3K11 x HPK1

更新于：2024-11-01

基本信息

关联

项与 MAP3K11 x HPK1 相关的药物

MD300

靶点

HPK1 x MAP3K11

作用机制

HPK1抑制剂 [+1]

在研机构

MD Biolab Co., Ltd.

原研机构

MD Biolab Co., Ltd.

在研适应症

肿瘤

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 MAP3K11 x HPK1 相关的临床结果

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100 项与 MAP3K11 x HPK1 相关的转化医学

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0 项与 MAP3K11 x HPK1 相关的专利（医药）

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项与 MAP3K11 x HPK1 相关的文献（医药）

2022-08-01·Journal of Biological Chemistry

Phosphorylation of mixed lineage kinase MLK3 by cyclin-dependent kinases CDK1 and CDK2 controls ovarian cancer cell division

Article

作者: Honda, David ; Taylor, William R ; Lewandowski, Mark D ; Cedeno-Rosario, Luis ; Chadee, Deborah N ; Sunderland, Autumn M

Mixed lineage kinase 3 (MLK3) is a serine/threonine mitogen-activated protein kinase kinase kinase that promotes the activation of multiple mitogen-activated protein kinase pathways and is required for invasion and proliferation of ovarian cancer cells. Inhibition of MLK activity causes G2/M arrest in HeLa cells; however, the regulation of MLK3 during ovarian cancer cell cycle progression is not known. Here, we found that MLK3 is phosphorylated in mitosis and that inhibition of cyclin-dependent kinase 1 (CDK1) prevented MLK3 phosphorylation. In addition, we observed that c-Jun N-terminal kinase, a downstream target of MLK3 and a direct target of MKK4 (SEK1), was activated in G2 phase when CDK2 activity is increased and then inactivated at the beginning of mitosis concurrent with the increase in CDK1 and MLK3 phosphorylation. Using in vitro kinase assays and phosphomutants, we determined that CDK1 phosphorylates MLK3 on Ser548 and decreases MLK3 activity during mitosis, whereas CDK2 phosphorylates MLK3 on Ser770 and increases MLK3 activity during G1/S and G2 phases. We also found that MLK3 inhibition causes a reduction in cell proliferation and a cell cycle arrest in ovarian cancer cells, suggesting that MLK3 is required for ovarian cancer cell cycle progression. Taken together, our results suggest that phosphorylation of MLK3 by CDK1 and CDK2 is important for the regulation of MLK3 and c-Jun N-terminal kinase activities during G1/S, G2, and M phases in ovarian cancer cell division.

2022-03-18·Science Advances1区 · 综合性期刊

Membrane repair triggered by cholesterol-dependent cytolysins is activated by mixed lineage kinases and MEK

1区 · 综合性期刊

ArticleOA

作者: Roth, Robyn ; Keyel, Peter A. ; Ray, Sucharit

Repair of plasma membranes damaged by bacterial pore-forming toxins, such as streptolysin O or perfringolysin O, during septic cardiomyopathy or necrotizing soft tissue infections is mediated by several protein families. However, the activation of these proteins downstream of ion influx is poorly understood. Here, we demonstrate that following membrane perforation by bacterial cholesterol-dependent cytolysins, calcium influx activates mixed lineage kinase 3 independently of protein kinase C or ceramide generation. Mixed lineage kinase 3 uncouples mitogen-activated kinase kinase (MEK) and extracellular-regulated kinase (ERK) signaling. MEK signals via an ERK-independent pathway to promote rapid annexin A2 membrane recruitment and enhance microvesicle shedding. This pathway accounted for 70% of all calcium ion-dependent repair responses to streptolysin O and perfringolysin O, but only 50% of repair to intermedilysin. We conclude that mixed lineage kinase signaling via MEK coordinates microvesicle shedding, which is critical for cellular survival against cholesterol-dependent cytolysins.

2018-02-01·Oncogene1区 · 医学

MLK3 phosphorylation by ERK1/2 is required for oxidative stress-induced invasion of colorectal cancer cells

1区 · 医学

Article

作者: Schroyer, A L ; Chadee, D N ; Abi Saab, W F ; Stimes, N W

Mixed lineage kinase 3 (MLK3) functions in migration and/or invasion of several human cancers; however, the role of MLK3 in colorectal cancer (CRC) invasion is unknown. MLK3 is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) which activates MAPK pathways through either kinase-dependent or -independent mechanisms. Human colorectal tumors display increased levels of reactive oxygen species (ROS) or oxidative stress. ROS, such as H₂O₂, are important for carcinogenesis and activate MAPK signaling pathways. In human colorectal carcinoma (HCT116) cells treated with H₂O₂, extracellular signal-regulated kinases 1 and 2 (ERK1/2) were activated and MLK3 exhibited reduced electrophoretic mobility (shift) in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), which was eliminated by phosphatase treatment. Pretreatment with the ROS scavenger N-acetyl-L-cysteine, the ERK1/2 inhibitor UO126, or ERK1/2 siRNA knockdown blocked the H₂O₂-induced shift of MLK3, while MLK3 inhibition with Cep1347 did not. In co-immunoprecipitation experiments performed on H₂O₂-treated HCT116 cells, endogenous MLK3 associated with endogenous ERK1/2 and B-Raf. Active ERK1 phosphorylated kinase dead FLAG-MLK3 in vitro, whereas ERK1 phosphorylation of kinase dead FLAG-MLK3-S705A-S758A was reduced. Both MLK3 siRNA knockdown and FLAG-MLK3-S705A-S758A expression decreased ERK1/2 activation in H₂O₂-treated cells. Prolonged H₂O₂ treatment activated ERK1/2 and promoted invasion of colon cancer cells, which was attenuated by MLK3 siRNA knockdown. Furthermore, S705A-S758A-FLAG-MLK3 demonstrated decreased oxidative-stress induced colon cancer cell invasion, but increased interaction with GST-B-Raf as compared with wild-type-FLAG-MLK3 in H₂O₂-treated cells. These results suggest oxidative stress stimulates an ERK1/2-dependent phosphorylation of MLK3 on Ser⁷⁰⁵ and Ser⁷⁵⁸, which promotes MLK3-dependent B-Raf and ERK1/2 activation; this positive feedback loop enhances the invasion of colon cancer cells.