PI3K-related kinases

PI3K-related kinases
Name	PI3K-related kinases
Family	Serine/threonine-protein kinases

PI3K-related kinases are a conserved group of large serine/threonine protein kinases related by sequence and structural homology to phosphoinositide 3-kinases. They coordinate cellular responses to DNA damage, growth factor signals, and nutrient availability, integrating inputs from pathways studied by researchers at institutions such as Cold Spring Harbor Laboratory, European Molecular Biology Laboratory, and Dana–Farber Cancer Institute. Prominent investigators and prize-winning laboratories associated with their discovery and characterization include teams from Massachusetts Institute of Technology, Harvard University, and recipients of awards like the Lasker Award.

Overview

PI3K-related kinases were identified through comparative genomics in studies by groups at National Institutes of Health and Max Planck Society and first functionally linked to DNA repair and cell cycle control in work from laboratories at Broad Institute and University of Cambridge. Members share evolutionary relationships highlighted in phylogenetic analyses performed by researchers at Wellcome Trust Sanger Institute and European Bioinformatics Institute, and have been central to translational programs at organizations such as National Cancer Institute and Cancer Research UK. Major reviews synthesizing their biology have appeared from contributors affiliated with Johns Hopkins University, UCSF, and Stanford University School of Medicine.

Structure and Domain Architecture

The catalytic core of PI3K-related kinases resembles the kinase domain characterized in structural studies from groups at Protein Data Bank depositors like RCSB, with the conserved ATR/ATM/TRRAP-related motifs delineated by cryo-EM teams at Max Planck Institute for Biochemistry and crystallography labs at European Synchrotron Radiation Facility. Flanking domains include tandem HEAT repeats resolved in complexes studied by Cold Spring Harbor Laboratory collaborators, FAT and FATC regions described by investigators at University of Oxford, and PIKK regulatory domains mapped in electron microscopy projects led by Cryo-EM National Center affiliates. Comparative domain mapping across species was performed using resources from Ensembl and UniProt.

Classification and Family Members

Major family members include ATR (ataxia telangiectasia and Rad3-related), ATM (ataxia telangiectasia mutated), DNA-PKcs (DNA-dependent protein kinase catalytic subunit), mTOR (mechanistic target of rapamycin), SMG1, and TRRAP, each annotated and curated by databases such as RefSeq and Gene Ontology Consortium. Landmark genetic characterizations were conducted by teams at Mayo Clinic, Imperial College London, and Yale University, while cancer genomics consortia like The Cancer Genome Atlas and International Cancer Genome Consortium catalog recurrent alterations. Functional nomenclature and ortholog identification have been standardized through collaborations between HUGO Gene Nomenclature Committee and Mouse Genome Informatics.

Biological Functions and Signaling Pathways

PI3K-related kinases orchestrate DNA damage response signaling cascades described in mechanistic studies from Cold Spring Harbor Laboratory and Salk Institute, phosphorylating effector proteins characterized by investigators at Memorial Sloan Kettering Cancer Center and Beth Israel Deaconess Medical Center. mTOR integrates signals from insulin receptor pathways and nutrient sensors elucidated by work at University of California, Berkeley and Karolinska Institute, impacting processes studied at Max Delbrück Center and Institute Pasteur. ATM and ATR activate checkpoint kinases whose substrates were mapped in phosphoproteomics projects affiliated with European Molecular Biology Laboratory and Stanford Medicine, connecting to cell fate decisions explored at Columbia University and University of Pennsylvania.

Regulation and Post-translational Modifications

Regulatory mechanisms include phosphorylation cycles discovered in signaling studies from Howard Hughes Medical Institute investigators, ubiquitin-mediated control analyzed by groups at University of Tokyo and Cold Spring Harbor Laboratory, and acetylation events reported from teams at Weizmann Institute of Science. Interaction with regulatory complexes such as RUVBL1/2 was shown by research from University of Geneva, while inhibitor-bound structures informing regulatory states were solved by consortia at European Molecular Biology Laboratory and EMBL-EBI. Crosstalk with pathways studied at Scripps Research and Max Planck Society further modulates activity through reversible modifications identified in mass spectrometry facilities at Broad Institute.

Roles in Disease and Therapeutic Targeting

Mutations and dysregulation of PI3K-related kinases contribute to ataxia-telangiectasia phenotypes characterized in clinical centers like Johns Hopkins Hospital and Great Ormond Street Hospital, and drive oncogenic processes cataloged by Memorial Sloan Kettering Cancer Center and Dana–Farber Cancer Institute. mTOR inhibitors developed through industry-academic partnerships involving companies collaborating with National Institutes of Health have been evaluated in trials registered by networks such as European Society for Medical Oncology and American Society of Clinical Oncology. DNA-PKcs and ATM are targeted by small molecules and biologics under investigation in translational programs at Vanderbilt University Medical Center and Fred Hutchinson Cancer Center; resistance mechanisms have been explored in consortia including Stand Up To Cancer.

Experimental Methods and Research Tools

Key methods include cryo-electron microscopy used by facilities at EMBL and Max Planck Institute, X-ray crystallography performed at stations such as Diamond Light Source, and phosphoproteomics executed in core facilities at Whitehead Institute and Broad Institute. Genetic tools include CRISPR screens implemented by groups at MIT and Broad Institute, mouse models developed through repositories at Jackson Laboratory, and chemical probes synthesized in collaborations with Novartis and Roche. Databases and bioinformatics pipelines supporting research are maintained by UniProt, Ensembl, and Gene Expression Omnibus.

Category:Protein kinases Category:DNA repair Category:Signal transduction