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Last update 08 May 2025

ULK3

Last update 08 May 2025

Basic Info

Synonyms

DKFZP434C131, FLJ90566, Serine/threonine-protein kinase ULK3

+ [4]

Introduction

Serine/threonine protein kinase that acts as a regulator of Sonic hedgehog (SHH) signaling and autophagy. Acts as a negative regulator of SHH signaling in the absence of SHH ligand: interacts with SUFU, thereby inactivating the protein kinase activity and preventing phosphorylation of GLI proteins (GLI1, GLI2 and/or GLI3). Positively regulates SHH signaling in the presence of SHH: dissociates from SUFU, autophosphorylates and mediates phosphorylation of GLI2, activating it and promoting its nuclear translocation. Phosphorylates in vitro GLI2, as well as GLI1 and GLI3, although less efficiently. Also acts as a regulator of autophagy: following cellular senescence, able to induce autophagy.

Drugs associated with ULK3

MA9-060

Target

BRD4 x ULK3

Mechanism

BRD4 inhibitors [+1]

Active Org.

H. Lee Moffitt Cancer Center & Research Institute, Inc.

Originator Org.

H. Lee Moffitt Cancer Center & Research Institute, Inc.

Active Indication

Multiple Myeloma [+1]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ULK3

100 Translational Medicine associated with ULK3

0 Patents (Medical) associated with ULK3

Literatures (Medical) associated with ULK3

01 Jun 2025·Journal of Pharmaceutical and Biomedical Analysis

Identification of potential drug targets for four site-specific cancers by integrating human plasma proteome with genome

Article

Author: Sun, Ziyi ; Tian, Shaodan ; Yun, Zhangjun ; Li, Xiao ; Hou, Li ; Yan, Xiang ; Yang, Qianru ; Liu, Zhu

Drug targets supported by genetic evidence with a several-fold higher probability of success in clinical trials. We performed a comprehensive proteome-wide Mendelian randomization (MR) analysis to identify causal proteins and potential therapeutic targets for four site-specific cancers. A total of 13,248 protein quantitative trait loci for 4853 plasma proteins were utilized for proteome-wide MR analysis. Identification of cancer causal proteins in the discovery cohort and further validation in the replication cohort. Colocalization, summary-data-based MR (SMR) analysis, and transcriptome‑wide association studies (TWAS) were performed to check the accuracy of the candidate proteins. Two-step MR analysis was used to explore the effects of plasma protein-mediated 248 modifiable factors on cancer. Phenome-wide MR (Phe-MR) analysis, druggability evaluation, and single-cell type expression analysis further assessed the potential of causal proteins. Combining the results of the meta-analysis of MR estimates from the two cohorts, 21, 2, 24 and 1 causal proteins were identified in breast, lung, prostate and stomach cancers, respectively. Evidence from colocalization, SMR analysis, and TWAS highlighted CD36, DNPH1, and PLXND1 as the most promising drug targets for breast cancer, and ZNF175 for prostate cancer. 1 new potential biomarker (PLXND1) for breast cancer, 2 new promising targets (RELL1, DEFB119) for lung cancer, and 8 new circulating biomarkers (ARFIP2, CCN6, CTRB2, HTR7, MRPL33, TNFRSF6B, VAMP5, ZNF175) for prostate cancer were firstly reported. Some plasma proteins may mediate the association of these cancers with other systemic diseases. Additionally, genetically predicted higher BMI and overweight may reduce breast cancer risk by altering CASP8, ADM, PLXND1, TNFRSF9, ULK3 and VSIG4 protein levels. Causal proteins of breast and prostate cancer were expressed predominantly on macrophages in cancerous tissues. This study genetically identified several cancer causal proteins which provided new perspectives for the understanding of the etiology and development of novel targeted drugs for cancer.

10 Jan 2025·Science Advances

Morphogen-induced kinase condensates transduce Hh signal by allosterically activating Gli

Article

Author: Wang, Bing ; Zhou, Mengmeng ; Jiang, Jin ; Han, Yuhong

Hedgehog (Hh) morphogen governs embryonic development and tissue homeostasis through the Ci/Gli family transcription factors. Here we report that Hh induces phase separation of the fused (Fu)/Ulk family kinases to allosterically regulate Ci/Gli. We find that Hh-induced phosphorylation of Fu/Ulk3 promotes SUMOylation of their inverted phosphorylation-dependent SUMOylation motifs. Subsequent interaction between SUMO and SUMO-interacting motif drives Fu/Ulk3 self-assembly to form biomolecular condensates that recruit Ci-Sufu and Gli-Sufu in the cytoplasm and primary cilium, respectively. Within the condensates, Fu/Ulk3 undergoes a conformational change to expose Ci/Gli for Fu/Ulk3-mediated phosphorylation and activation, leading to gradual accumulation of nuclear Ci A /Gli A transcriptional complexes in proportion to ligand dose and exposure time. Our findings provide mechanistic insights into the spatiotemporal control of Hh signal transduction, reveal previously unexplored regulatory mechanism and function for biomolecular condensation, and establish a paradigm for kinase-mediated signal transduction whereby a kinase allosterically activates its substrate through ligand-induced and condensation-driven conformational change.

02 Jan 2025·Autophagy

BIN1 deficiency enhances ULK3-dependent autophagic flux and reduces dendritic size in mouse hippocampal neurons

Article

Author: Sheng, Chengyu ; Li, Qian ; Shi, Huili ; Chen, Tingzhen ; Zhang, Guannan ; Cao, Haifeng ; Gao, Junying ; Ding, Shixin ; Chen, Sijia ; Zhang, Yanli ; Jin, Yuxi ; Xiao, Ming ; Sun, Huaiqing ; Zhao, Lin

Genome-wide association studies identified variants around the BIN1 (bridging integrator 1) gene locus as prominent risk factors for late-onset Alzheimer disease. In the present study, we decreased the expression of BIN1 in mouse hippocampal neurons to investigate its neuronal function. Bin1 knockdown via RNAi reduced the dendritic arbor size in primary cultured hippocampal neurons as well as in mature Cornu Ammonis 1 excitatory neurons. The AAV-mediated Bin1 RNAi knockdown also generated a significant regional volume loss around the injection sites at the organ level, as revealed by 7-Tesla structural magnetic resonance imaging, and an impaired spatial reference memory performance in the Barnes maze test. Unexpectedly, Bin1 knockdown led to concurrent activation of both macroautophagy/autophagy and MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1). Autophagy inhibition with the lysosome inhibitor chloroquine effectively mitigated the Bin1 knockdown-induced dendritic regression. The subsequent molecular studydemonstrated that increased expression of ULK3 (unc-51 like kinase 3), which is MTOR-insensitive, supported autophagosome formation in BIN1 deficiency. Reducing ULK3 activity with SU6668, a receptor tyrosine kinase inhibitor, or decreasing neuronal ULK3 expression through AAV-mediated RNAi, significantly attenuated Bin1 knockdown-induced hippocampal volume loss and spatial memory decline. In Alzheimer disease patients, the major neuronal isoform of BIN1 is specifically reduced. Our work suggests this reduction is probably an important molecular event that increases the autophagy level, which might subsequently promote brain atrophy and cognitive impairment through reducing dendritic structures, and ULK3 is a potential interventional target for relieving these detrimental effects.Abbreviations: AV: adeno-associated virus; Aβ: amyloid-β; ACTB: actin, beta; AD: Alzheimer disease; Aduk: Another Drosophila Unc-51-like kinase; AKT1: thymoma viral proto-oncogene 1; AMPK: AMP-activated protein kinase; AP: autophagosome; BafA1: bafilomycin A₁; BDNF: brain derived neurotrophic factor; BIN1: bridging integrator 1; BIN1-iso1: BIN1, isoform 1; CA1: cornu Ammonis 1; CA3: cornu Ammonis 3; CLAP: clathrin and adapter binding; CQ: chloroquine; DMEM: Dulbecco's modified Eagle medium; EGFP: enhanced green fluorescent protein; GWAS: genome-wide association study; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MRI: magnetic resonance imaging; MTOR; mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; PET: positron emission tomography; qRT-PCR: real-time quantitative reverse transcription PCR; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; TFEB: transcription factor EB; ULK1: unc-51 like kinase 1; ULK3: unc-51 like kinase 3.

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ULK3

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