Last update 01 Nov 2024

MAP3K11

Last update 01 Nov 2024

Basic Info

Synonyms

MAP3K11, MEKK11, Mitogen-activated protein kinase kinase kinase 11

+ [5]

Introduction

Activates the JUN N-terminal pathway. Required for serum-stimulated cell proliferation and for mitogen and cytokine activation of MAPK14 (p38), MAPK3 (ERK) and MAPK8 (JNK1) through phosphorylation and activation of MAP2K4/MKK4 and MAP2K7/MKK7. Plays a role in mitogen-stimulated phosphorylation and activation of BRAF, but does not phosphorylate BRAF directly. Influences microtubule organization during the cell cycle.

Drugs associated with MAP3K11

CEP1347-VHL-02

Target

MAP3K11

Mechanism

MAP3K11 inhibitors

Active Org.

Instytut Immunologii i Terapii Doswiadczalnej [+1]

Originator Org.

National Institutes of Health [+1]

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

MD300

Target

HPK1 x MAP3K11

Mechanism

HPK1 inhibitors [+1]

Active Org.

MD Biolab Co., Ltd.

Originator Org.

MD Biolab Co., Ltd.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

OST-246

Target

JAK3 x MAP3K11 x TYK2

Mechanism

JAK3 inhibitors [+2]

Active Org.

Oncostellae SL

Originator Org.

Oncostellae SL

Active Indication

Autoimmune Diseases [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with MAP3K11

EUCTR2004-002812-27-IS / Not yet recruitingPhase 2

A prospective, randomised, double-blind, placebo-controlled, parallel group dose ranging study in asthma patients in Iceland to assess the safety, tolerability and efficacy of the MLK inhibitor, CEP-1347

Start Date04 May 2005

Sponsor / Collaborator

deCODE Genetics ehf

NCT00040404 / TerminatedPhase 2/3

A Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study to Assess the Efficacy and Safety of CEP-1347 in Patients With Parkinson's Disease

The purpose of this study is to establish safety for CEP-1347 and to determine an efficacious dose in the treatment of Parkinson's disease.

Start Date01 Mar 2002

Sponsor / Collaborator

Cephalon, Inc.

[+2]

100 Clinical Results associated with MAP3K11

100 Translational Medicine associated with MAP3K11

0 Patents (Medical) associated with MAP3K11

662

Literatures (Medical) associated with MAP3K11

31 Dec 2024·International Journal of Hyperthermia

Deregulated JNK signaling enhances apoptosis during hyperthermia

Article

Author: Sato, Shinichi ; Nakagawa, Keiichi ; Miyagawa, Kiyoshi ; Yoshizaki, Ayumi ; Hosoya, Noriko ; Terunuma, Hiroshi ; Enomoto, Atsushi ; Fukasawa, Takemichi

PURPOSEc-Jun N-terminal kinases (JNKs) comprise a subfamily of mitogen-activated protein kinases (MAPKs). The JNK group is known to be activated by a variety of stimuli. However, the molecular mechanism underlying heat-induced JNK activation is largely unknown. The aim of this study was to clarify how JNK activity is stimulated by heat.METHODS AND MATERIALSThe expression levels of various MAPK members in HeLa cells, with or without hyperthermia treatment, were evaluated via western blotting. The kinase activity of MAPK members was assessed through in vitro kinase assays. Cell death was assessed in the absence or presence of siRNAs targeting MAPK-related members.RESULTSHyperthermia decreased the levels of MAP3Ks, such as ASK1 and MLK3 which are JNK kinase kinase members, but not those of the downstream MAP2K/SEK1 and MAPK/JNK. Despite the reduced or transient phosphorylation of ASK1, MLK3, or SEK1, downstream JNK was phosphorylated in a temperature-dependent manner. In vitro kinase assays demonstrated that heat did not directly stimulate SEK1 or JNK. However, the expression levels of DUSP16, a JNK phosphatase, were decreased upon hyperthermia treatment. DUSP16 knockdown enhanced the heat-induced activation of ASK1-SEK1-JNK pathway and apoptosis.CONCLUSIONJNK was activated in a temperature-dependent manner despite reduced or transient phosphorylation of the upstream MAP3K and MAP2K. Hyperthermia-induced degradation of DUSP16 may induce activation of the ASK1-SEK1-JNK pathway and subsequent apoptosis.

01 Dec 2024·Cellular and Molecular Life Sciences

Disrupting PIAS3-mediated SUMOylation of MLK3 ameliorates poststroke neuronal damage and deficits in cognitive and sensorimotor behaviors

Article

Author: Hu, Lulu ; Shao, Mengwen ; Chen, Rourou ; Zhang, Bingge ; Meng, Li ; Xu, Yan ; Jiang, Yu ; Wang, Baixue ; Du, Caiping ; Li, Meng

AbstractActivated small ubiquitin-like modifiers (SUMOs) have been implicated in neuropathological processes following ischemic stroke. However, the target proteins of SUMOylation and their contribution to neuronal injury remain to be elucidated. MLK3 (mixed-lineage kinase 3), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, is a critical regulator of neuronal lesions following cerebral ischemia. Here, we found that SUMOylation of MLK3 increases in both global and focal ischemic rodent models and primary neuronal models of oxygen and glucose deprivation (OGD). SUMO1 conjugation at the Lys401 site of MLK3 promoted its activation, stimulated its downstream p38/c-Jun N-terminal kinase (JNK) cascades, and led to cell apoptosis. The interaction of MLK3 with PIAS3, a SUMO ligase, was elevated following ischemia and reperfusion. The PINIT domain of PIAS3 was involved in direct interactions with MLK3. Overexpression of the PINIT domain of PIAS3 disrupted the MLK3-PIAS3 interaction, inhibited SUMOylation of MLK3, suppressed downstream signaling, and reduced cell apoptosis and neurite damage. In rodent ischemic models, the overexpression of the PINIT domain reduced brain lesions and alleviated deficits in learning, memory, and sensorimotor functions. Our findings demonstrate that brain ischemia-induced MLK3 SUMOylation by PIAS3 is a potential target against poststroke neuronal lesions and behavioral impairments.

01 Oct 2024·Stem Cell Research

Generation of induced pluripotent stem cell line (UCSFi001-A-77) carrying a biallelic frameshift variant in exon 4 of SGIP1 through CRISPR/Cas9

Article

Author: van Bokhoven, Hans ; de Brouwer, Arjan P M ; Albert, Silvia ; van Beusekom, Ellen ; Ali Khan, Asma ; Çepni, Ece ; Hommersom, Marina P ; Fatima, Fareeha ; Fatima, Neelam ; Dillen, Lieke

SGIP1 encodes a protein Src homology 3-domain growth factor receptor-bound 2-like endophilin interacting protein 1. It is involved in the regulation of clathrin-mediated endocytosis along with having a role in energy homeostasis in neuronal systems. We generated an isogenic human induced pluripotent stem cell (iPSC) line with a biallelic frameshift variant in SGIP1. This exon has been shown to be subject to alternative splicing, leading to an isoform lacking 24 amino acids that are present in the longest SGIP isoform. The newly generated iPSC line will be helpful to dissect the differential properties of the two SGIP isoforms.

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MAP3K11

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