Last update 01 Nov 2024

MLK subfamily x MAP3K12

Last update 01 Nov 2024

Basic Info

Related Targets

MLK subfamilyMAP3K12

Drugs associated with MLK subfamily x MAP3K12

Kinase inhibitors(Califia/URMC)

Target

MAP3K12 x MLK subfamily

Mechanism

MAP3K12 inhibitors [+1]

Active Org.-

Originator Org.

Califia Bio, Inc.

Active Indication-

Inactive Indication

Diabetic Neuropathies [+1]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with MLK subfamily x MAP3K12

NL-OMON51028 / RecruitingNot ApplicableIIT

The effect of JAnus KinAse inhibitors on the heart in RheumaToid Arthritis - JAKARTA

Start Date07 Mar 2022

Sponsor / Collaborator

Stichting Reade Foundation

100 Clinical Results associated with MLK subfamily x MAP3K12

100 Translational Medicine associated with MLK subfamily x MAP3K12

0 Patents (Medical) associated with MLK subfamily x MAP3K12

Literatures (Medical) associated with MLK subfamily x MAP3K12

28 Jan 2022·Oncogene

Elevated expression of RIT1 hyperactivates RAS/MAPK signal and sensitizes hepatocellular carcinoma to combined treatment with sorafenib and AKT inhibitor

Article

Author: Zhou, Zhengdong ; Yang, Hui ; Shi, Chaoran ; Guan, Xin-Yuan ; Zhang, Yu ; Sun, Liangzhan ; Zheng, Jingyi ; Du, Yuyang ; Yu, Dandan ; Xi, Shaoyan ; Hu, Pengchao ; Wu, Shasha ; Chen, Miao ; Zhang, Feifei ; Li, Yan ; Yan, Qian ; Wang, Ying ; Xie, Dan ; Wang, Yanchen ; Wu, Shayi ; Cui, Yuzhu

Hyperactivation of RAS/MAPK signaling is commonly observed in hepatocellular carcinoma (HCC). Gain-of-function mutations of canonical RAS genes, however, are rarely detected and it remains unclear how the activity of this pathway is turned on during hepatocarcinogenesis. We performed a comprehensive analysis of RAS superfamily genetic alterations across ten subfamilies, 152 members in 377 HCC patients from the Cancer Genome Atlas database. RIT1 (Ras-like without CAAX 1) was the most frequently altered RAS member amplified in 13% of the HCC cohort. Both genomic amplification and CREB-mediated transcriptional activation contributed to the elevated RIT1 expression, and its overexpression correlated with RAS/MAPK activation and poor prognosis. Then, we found that RIT1-induced angiogenesis via the MEK/ERK/EIF4E/HIF1-α/VEGFA axis. MAP3K11 and MAP3K12, in addition to CRAF, could mediate this process by binding to RIT1. Moreover, RIT1 increased the phosphorylation of p38 MAPK and AKT to promote cell survival under reactive oxygen species stress. Based on this mechanistic understanding, we treated RIT1-overexpressing HCC with combined regimen sorafenib plus AKT inhibitor, and achieved enhanced antitumor effects in vivo. Our study reveals RAS "orphan" member RIT1 as the most common genetic alteration of RAS family in HCC and combination of sorafenib with AKT inhibitor might be a promising treatment strategy for RIT1-overexpressing HCC.

01 Apr 2016·Cellular SignallingQ3 · BIOLOGY

Distinct functions of the dual leucine zipper kinase depending on its subcellular localization

Q3 · BIOLOGY

Article

Author: Miosge, Nicolai ; Blume, Roland ; Babaeikelishomi, Rohollah ; Maedler, Kathrin ; Stahnke, Marie-Jeannette ; Kruegel, Jenny ; Schröder, Sabine ; Wallbach, Manuel ; Duque Escobar, Jorge ; Kluth, Oliver ; Oetjen, Elke ; Kehlenbach, Ralph H

The dual leucine zipper kinase DLK induces β-cell apoptosis by inhibiting the transcriptional activity conferred by the β-cell protective transcription factor cAMP response element binding protein CREB. This action might contribute to β-cell loss and ultimately diabetes. Within its kinase domain DLK shares high homology with the mixed lineage kinase (MLK) 3, which is activated by tumor necrosis factor (TNF) α and interleukin (IL)-1β, known prediabetic signals. In the present study, the regulation of DLK in β-cells by these cytokines was investigated. Both, TNFα and IL-1β induced the nuclear translocation of DLK. Mutations within a putative nuclear localization signal (NLS) prevented basal and cytokine-induced nuclear localization of DLK and binding to the importin receptor importin α, thereby demonstrating a functional NLS within DLK. DLK NLS mutants were catalytically active as they phosphorylated their down-stream kinase c-Jun N-terminal kinase to the same extent as DLK wild-type but did neither inhibit CREB-dependent gene transcription nor transcription conferred by the promoter of the anti-apoptotic protein BCL-xL. In addition, the β-cell apoptosis-inducing effect of DLK was severely diminished by mutation of its NLS. In a murine model of prediabetes, enhanced nuclear DLK was found. These data demonstrate that DLK exerts distinct functions, depending on its subcellular localization and thus provide a novel level of regulating DLK action. Furthermore, the prevention of the nuclear localization of DLK as induced by prediabetic signals with consecutive suppression of β-cell apoptosis might constitute a novel target in the therapy of diabetes mellitus.

16 Jan 2008·The Journal of NeuroscienceQ1 · MEDICINE

Antiapoptotic and Trophic Effects of Dominant-Negative Forms of Dual Leucine Zipper Kinase in Dopamine Neurons of the Substantia NigraIn Vivo

Q1 · MEDICINE

Article

Author: Kareva, Tatyana ; Bland, Ross ; During, Matthew J. ; Burke, Robert E. ; Kholodilov, Nikolai ; Tank, A. William ; Rzhetskaya, Margarita ; Chen, Xiqun

There is extensive evidence that the mitogen-activated protein kinase (MAPK) signaling cascade mediates programmed cell death in neurons. However, current evidence that the mixed linage kinases (MLKs), upstream in this cascade, mediate cell death is based, in thein vivocontext, entirely on pharmacological approaches. The compounds used in these studies have neither complete specificity nor selectivity among these kinases. Therefore, to better address the molecular specificity of the MLKs in mediating neuron death, we used dominant-negative constructs delivered by AAV (adenoassociated virus) vector transfer. We assessed effects in a neurotoxin model of parkinsonism, in which neuroprotection by pharmacologic MLK inhibition has been reported. We find that two dominant-negative forms of dual leucine zipper kinase (DLK) inhibit apoptosis and enhance long-term survival of dopamine neurons, but a dominant negative of MLK3 does not. Interestingly, the kinase-dead form of DLK not only blocks apoptosis but also has trophic effects on dopamine neurons. Although the MAPK cascade activates a number of downstream cell death mediators, we find that inhibition of DLK correlates closely with blockade of phosphorylation of c-jun and prevention of cell death. We conclude that DLK acts primarily through c-jun phosphorylation to mediate cell death in this model.

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