Kinases

  • Article
    | Open Access

    Elucidating specific effects of protein kinase Akt isoforms remains challenging. Here, the authors establish an Akt isoform-dependent cellular model system and use it, together with X-ray crystallography and structure-based ligand design, to develop isoform-selective covalent-allosteric Akt inhibitors

    • Lena Quambusch
    • , Laura Depta
    •  & Daniel Rauh
  • Article
    | Open Access

    The bacteriophytochrome DrBphP from Deinococcus radiodurans shows high sequence homology to the histidine kinase Agp1 from Agrobacterium fabrum but lacks kinase activity. Here, the authors structurally and biochemically analyse DrBphP and Agp1, showing that DrBphP is a light-activatable phosphatase.

    • Elina Multamäki
    • , Rahul Nanekar
    •  & Heikki Takala
  • Article
    | Open Access

    The intracellular compartment is a crowded environment. Here, the authors use molecular dynamics (MD) simulations to assess inhibitor binding to c-Src kinase and show how ligand binding pathways differ in crowded and dilute protein solutions, highlighting the role of c-Src Tyr82 sidechain.

    • Kento Kasahara
    • , Suyong Re
    •  & Yuji Sugita
  • Article
    | Open Access

    Activation of c-MET receptor tyrosine kinase involves hepatocyte growth factor (HGF) and glycosaminoglycans, but the molecular mechanism is still under debate. Here, the authors present cryoEM structures of c-MET bound to two HGF splice variants and heparin, revealing the structural basis for c-MET activation.

    • Emiko Uchikawa
    • , Zhiming Chen
    •  & Xiao-chen Bai
  • Article
    | Open Access

    Host cell invasion by Toxoplasma gondii depends on the heavily phosphorylated RON complex, but the relevance and regulation of these modifications are not understood. Here, the authors identify the kinase RON13 as a key virulence factor, determine its structure and show that it phosphorylates the RON complex.

    • Gaëlle Lentini
    • , Rouaa Ben Chaabene
    •  & Dominique Soldati-Favre
  • Article
    | Open Access

    The mechanistic target of rapamycin complex 1 (mTORC1) integrates nutrient and hormonal signals to control metabolism. Here the authors investigate the effects of constitutive nutrient signaling through genetic activation of RagA in adult mice and show that constitutive nutrient signaling regulates the response to feeding-fasting cycles and does not drive liver cancer.

    • Celia de la Calle Arregui
    • , Ana Belén Plata-Gómez
    •  & Alejo Efeyan
  • Article
    | Open Access

    The IDG-DREAM Challenge carried out crowdsourced benchmarking of predictive algorithms for kinase inhibitor activities on unpublished data. This study provides a resource to compare emerging algorithms and prioritize new kinase activities to accelerate drug discovery and repurposing efforts.

    • Anna Cichońska
    • , Balaguru Ravikumar
    •  & Tero Aittokallio
  • Article
    | Open Access

    The circadian clock is an internal mechanism that controls various physiological processes, such as the sleep-wake cycle, but its precise regulation is challenging. Here, the authors develop a visible light-responsive inhibitor of casein kinase I which controls the period and phase of cellular and tissue circadian rhythms in a reversible manner.

    • Dušan Kolarski
    • , Carla Miró-Vinyals
    •  & Ben L. Feringa
  • Article
    | Open Access

    Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase is phosphorylated by RIPK3 kinase prior to cell death by necroptosis. Here, the authors use monobodies that bind to the MLKL pseudokinase domain as tools, which allowed them to determine the crystal structures of the MLKL pseudokinase domain in two distinct conformations. By combining their structural data with cell signalling assays and MD simulations they provide evidence that endogenous MLKL preassociates with its upstream regulator RIPK3, and that MLKL disengages from RIPK3 following the induction of necroptosis.

    • Sarah E. Garnish
    • , Yanxiang Meng
    •  & James M. Murphy
  • Article
    | Open Access

    The viral Protein Kinase-1 (PK-1) phosphorylates the regulatory protein p6.9, which facilitates baculoviral genome release. Here, the authors combine X-ray crystallography with biophysical and biochemical analyses as well as molecular dynamics simulations to characterize Cydia pomenella granulovirus PK-1, which forms a dimer with a parallel side-to-side arrangement of the kinase domains and furthermore, they provide insights into its catalytic mechanism and evolutionary relationships with other kinases.

    • Michael R. Oliver
    • , Christopher R. Horne
    •  & James M. Murphy
  • Article
    | Open Access

    The ATF2 transcription factor is phosphorylated by different mitogen-activated protein (MAP) kinases. Here, the authors show that the functionally distinct MAP kinases JNK and p38 control ATF2 through different binding sites and differential phosphorylation, thereby modulating ATF2’s sensitivity to the JNK and p38 pathways.

    • Klára Kirsch
    • , András Zeke
    •  & Attila Reményi
  • Article
    | Open Access

    Egress of flaviviruses and involved host pathways are not well understood. Here, the authors show that Lyn is a critical host kinase for Dengue and Zika virus egress resulting in infectious virus progenies within autophagosome-derived vesicles, which might help the virus to evade antibody responses.

    • Ming Yuan Li
    • , Trupti Shivaprasad Naik
    •  & Sumana Sanyal
  • Article
    | Open Access

    Herpesviruses code for conserved protein kinases (CHPKs) that exert several regulatory functions by interacting with cellular factors. Here, the authors use affinity purification mass spectrometry (AP–MS) to identify differential interaction partners of CHPKs from seven different human herpesviruses, finding Cyclin A and associated factors as a specific signature of β-herpesvirus kinases.

    • Boris Bogdanow
    • , Max Schmidt
    •  & Lüder Wiebusch
  • Article
    | Open Access

    FDA-approved RAF inhibitors poorly inhibit BRAF dimers, which limits their clinical efficacy in tumors expressing BRAFV600E mutant monomers. Here the authors identify FDA-approved Ponatinib as an effective inhibitor of BRAF monomers and dimers and designed PHI1, an inhibitor with a unique mode of action and selectivity for oncogenic BRAF dimers.

    • Xiomaris M. Cotto-Rios
    • , Bogos Agianian
    •  & Evripidis Gavathiotis
  • Article
    | Open Access

    Cell cycle checkpoint kinase, MK2, is in synthetic relationship with p53 in the DNA damage response to chemotherapeutic agents. Here, the authors report XPA as a third gene in which simultaneous targeting of MK2 and XPA further enhances sensitivity to cisplatin in p53-deficient tumours.

    • Yi Wen Kong
    • , Erik C. Dreaden
    •  & Michael B. Yaffe
  • Article
    | Open Access

    Plasmodium infection activates signaling pathways in a-nucleated erythrocytes. Here, Adderley et al. use a comprehensive antibody microarray to show that infection extensively modulates host cell signalling and that the host receptor tyrosine kinase c-MET supports Plasmodium falciparum proliferation.

    • Jack D. Adderley
    • , Simona John von Freyend
    •  & Christian Doerig
  • Article
    | Open Access

    Diseases can be associated with various mutations of the same gene, but the molecular consequences of specific mutations remain incompletely understood. Here, the authors present an integrated proteomic workflow to determine the molecular response of cells to different cancer-associated mutations of the kinase Dyrk2.

    • Martin Mehnert
    • , Rodolfo Ciuffa
    •  & Ruedi Aebersold
  • Article
    | Open Access

    Diamond Blackfan Anemia (DBA) is a congenital bone marrow failure syndrome that is associated with anemia. Here, the authors examine the role of Nemo-like kinase (NLK) in erythroid cells in the pathogenesis of DBA and as a potential target for therapy.

    • M. C. Wilkes
    • , K. Siva
    •  & K. M. Sakamoto
  • Article
    | Open Access

    Chemical tools to monitor drug-target engagement of endogenous enzymes are essential for preclinical target validation. Here, the authors present a chemical genetics strategy to study target engagement of endogenous kinases, achieving specific labeling and inactivation of FES kinase to provide insights into FES’ role in neutrophil phagocytosis.

    • Tom van der Wel
    • , Riet Hilhorst
    •  & Mario van der Stelt
  • Article
    | Open Access

    Cyclin-dependent kinase (CDK) inhibitors are widely used both in the clinic and for basic research aimed at dissecting the specific cellular functions of specific CDKs. Here, the authors report the development of a panel of fluorescent reporter probes and provide a comprehensive profile of the inhibitory activity of several CDK inhibitors towards all 21 CDKs in living cells.

    • Carrow I. Wells
    • , James D. Vasta
    •  & Matthew B. Robers
  • Article
    | Open Access

    Identifying kinases responsible for specific phosphorylation events remains challenging. Here, the authors leverage kinase inhibitor profiles for the identification of kinase-substrate site pairs in cell extracts, developing a method that can identify the enzymes responsible for unassigned phosphorylation events.

    • Nikolaus A. Watson
    • , Tyrell N. Cartwright
    •  & Jonathan M. G. Higgins
  • Article
    | Open Access

    In mitosis, Aurora B switches substrate specificity in response to phosphorylation of S227 in the activation loop by a cell cycle-processed active fragment of PKCε. Here, the authors show that this switch protects from chromosome non-disjunction by delaying anaphase entry and promoting TopoIIα-dependent resolution.

    • Joanna R. Kelly
    • , Silvia Martini
    •  & Tanya N. Soliman
  • Article
    | Open Access

    AMPK integrates information about a cell’s energy status to inform decisions about cellular processes, including autophagy. Here the authors identify cyclin Y as an AMPK substrate, which phosphorylates cyclin Y and promotes its interaction with CDK16 to stimulate autophagy.

    • Marc Dohmen
    • , Sarah Krieg
    •  & Jörg Vervoorts
  • Article
    | Open Access

    IKK2 is the main mediator of the NF-kappaB pathway. Here, the authors demonstrate that LMP1 sustains the survival of Epstein-Barr virus-transformed human B cells and post-transplant lymphoma through IKK2 that induces JNK signaling through TPL2.

    • Stefanie Voigt
    • , Kai R. Sterz
    •  & Arnd Kieser
  • Article
    | Open Access

    mTORC2 activates Akt, a regulator of cell growth and metabolism, however, the role of mTORC2 in adipocytes is incompletely understood. Here the authors report that a mTORC2-Akt axis specifically activates ACLY to promote lipid synthesis and histone acetylation during brown adipocyte differentiation.

    • C. Martinez Calejman
    • , S. Trefely
    •  & D. A. Guertin
  • Article
    | Open Access

    Here, Bhattacharya et al. chemically mutagenize Leishmania and identify genes associated with resistance to miltefosine and paromomycin by next generation sequencing. The study shows that a protein kinase (CDPK1) can mediate resistance to paromomycin by affecting translation.

    • Arijit Bhattacharya
    • , Philippe Leprohon
    •  & Marc Ouellette
  • Article
    | Open Access

    The chromosomal kinase JIL-1 is responsible for interphase histone H3S10 phosphorylation and has been proposed to protect active chromatin from heterochromatinisation. Here, the authors show that JIL-1 is stabilized and anchored to active genes and telomeric transposons by JASPer, which binds to H3K36me3 nucleosomes via its PWWP domain.

    • Christian Albig
    • , Chao Wang
    •  & Catherine Regnard
  • Article
    | Open Access

    The ERK signalling pathway is activated in many cancers, however ERK1 and ERK2 are difficult to target pharmacologically. Here, the authors identify a small molecule inhibitor that binds covalently to the D-recruitment site of ERK and induces cell death and reduces tumour growth in mice.

    • Tamer S. Kaoud
    • , William H. Johnson
    •  & Kevin N. Dalby
  • Article
    | Open Access

    Regulation of post translational modification of 53BP1 is critical for genome integrity and regulation of DNA damage response. Here the authors reveal a CDK5-PP4 phospho-signaling cascade that leads 53BP1 to sites of DNA damage.

    • Xiao-Feng Zheng
    • , Sanket S. Acharya
    •  & Dipanjan Chowdhury
  • Article
    | Open Access

    Protein kinase A (PKA) is a cyclic nucleotide dependent protein kinase. Here the authors use single molecule optical tweezers and steered molecular dynamic simulations to follow in real time and quantitatively characterize the signals transduced by cAMP through the structure of the PKA regulatory subunit, and propose a model for PKA allosteric activation.

    • Yuxin Hao
    • , Jeneffer P. England
    •  & Rodrigo A. Maillard
  • Article
    | Open Access

    The inner centromere protein (INCENP) activates Aurora kinase B (AURKB) and Aurora kinase C. Here the authors provide insights into the activation mechanism of AURKB/C by determining the crystal structure of fully active phosphorylated human AURKC bound to the phosphorylated C-terminal IN-box section of human INCENP.

    • Kamal R. Abdul Azeez
    • , Sneha Chatterjee
    •  & Jonathan M. Elkins
  • Article
    | Open Access

    β-propeller domains are an important class of folding substrates for the eukaryotic cytosolic chaperonin CTT. Here the authors find that CTT contributes to the folding and assembly of two β-propeller proteins from mTOR complexes, mLST8 and Raptor, and determine the 4.0 Å cryoEM structure of a human mLST8-CCT intermediate that shows mLST8 in a near-native state.

    • Jorge Cuéllar
    • , W. Grant Ludlam
    •  & José M. Valpuesta
  • Article
    | Open Access

    Colorectal cancer cells can acquire resistance to MEK inhibition due to BRAF or KRAS amplification. Here, the authors show that while MEK inhibitor withdrawal in BRAF mutant cells restores sensitivity to the inhibitor through the loss of BRAF amplification mediated by a p57-dependent mechanism, drug withdrawal from KRAS mutant cells does not restore sensitivity but results in EMT and chemoresistance.

    • Matthew J. Sale
    • , Kathryn Balmanno
    •  & Simon J. Cook
  • Article
    | Open Access

    During centriole duplication, Plk4 regulates formation of a single daughter centriole adjacent to the mother centriole, but the mechanism is unclear. Here, the authors show that Plk4 can undergo liquid–liquid phase separation and that the condensation properties are regulated by autophosphorylation.

    • Shohei Yamamoto
    •  & Daiju Kitagawa
  • Article
    | Open Access

    Hippo pathway inactivation plays a role in many cancers, although how tumor cells depress signaling is unclear. Here, Lim et al. identify STK25, which activates LATS in a manner distinct from other upstream kinases and is focally deleted from a range of human cancers.

    • Sanghee Lim
    • , Nicole Hermance
    •  & Neil J. Ganem
  • Article
    | Open Access

    Hyperactivation of Akt promotes tumorigenesis. Here, the authors show that SAV1, a member of Hippo signalling, interacts with Akt to suppress Akt activity and MERTK-mediated Akt phosphorylation relieves this suppression to facilitate Akt oncogenic activity in clear cell renal carcinomas.

    • Yao Jiang
    • , Yanqiong Zhang
    •  & Pengda Liu