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Article
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Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity
Coactivator-associated arginine methyltransferase 1 (CARM1) is an important target in hematologic malignancies. In this work, the authors show that the hyperactivation of Janus kinase 2 (JAK2) by the V617F mutation phosphorylates CARM1 which regulates its methyltransferase activity and alters its target specificity.
- Hidehiro Itonaga
- , Adnan K. Mookhtiar
- & Stephen D. Nimer
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Article
| Open Access
Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry
Unveiling the regulation of mitotic protein degradation is crucial for cancer therapy. Here, the authors reveal that a reciprocal inhibition of PIN1-APC/CCDH1 controls the cell cycle and mitotic protein degradation, offering a synergistic anti-tumor strategy.
- Shizhong Ke
- , Fabin Dang
- & Kun Ping Lu
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Article
| Open Access
Pathogenic mutations of human phosphorylation sites affect protein–protein interactions
Here the authors characterise the impact of phosphorylation site mutations in intrinsically disordered regions (IDRs) on protein-protein interactions, highlighting the critical role of phosphorylation of IDRs in health and disease.
- Trendelina Rrustemi
- , Katrina Meyer
- & Matthias Selbach
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Article
| Open Access
Dbf4-dependent kinase promotes cell cycle controlled resection of DNA double-strand breaks and repair by homologous recombination
The repair of DNA double strand breaks is strictly controlled during the cell cycle by the CDK kinase. Here the authors identify the DDK kinase as a second major regulator for this cell cycle regulation and elucidate its functional targets.
- Lorenzo Galanti
- , Martina Peritore
- & Boris Pfander
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Article
| Open Access
Casein kinase II promotes piRNA production through direct phosphorylation of USTC component TOFU-4
How the production of piRNA is regulated remains elusive. Here the authors showed that casein kinase II mediated direct phosphorylation of USTC component TOFU-4 promotes piRNA production.
- Gangming Zhang
- , Chunwei Zheng
- & Craig Mello
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Article
| Open Access
Therapeutic targeting nudix hydrolase 1 creates a MYC-driven metabolic vulnerability
MYC oncogene promotes tumourigenesis by coordinating cancer cell proliferation with metabolic adaptation to the consequent excessive oxidative stress. Here, the authors show that nudix hydrolase 1 (NUDT1) is a MYC-driven metabolic vulnerability and generate a NUDT1 protein degrader to treat preclinical MYC-associated cancer.
- Minhui Ye
- , Yingzhe Fang
- & Guoliang Qing
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Article
| Open Access
NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia
NME3 is a member of NDPK family. Here, Chen et. al., discover that histidine phosphorylatable NME3 is required for hypoxia-induced mitophagy via PA-dependent interaction with Drp1, which is protected from MUL1-mediated ubiquitination for mitophagy.
- Chih-Wei Chen
- , Chi Su
- & Zee-Fen Chang
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Article
| Open Access
The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation
The Eyes Absent proteins (EYA1-4) are a group of tyrosine phosphatases. Here, the authors report a signalling pathway in which EYA4 and EYA1 dephosphorylate Polo-like kinase 1 (PLK1) at pY445 to support PLK1 activation and mitosis.
- Christopher B. Nelson
- , Samuel Rogers
- & Hilda A. Pickett
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Article
| Open Access
The phosphatase DUSP22 inhibits UBR2-mediated K63-ubiquitination and activation of Lck downstream of TCR signalling
The T cell receptor signalosome integrates multiple positive and negative regulatory elements to finetune the response and limit harmful inflammation. Here authors show a regulatory cascade of T cell activation, in which DUSP22 negatively regulates UBR2, which is an activator of the kinase Lck via K63 ubiquitination.
- Ying-Chun Shih
- , Hsueh-Fen Chen
- & Tse-Hua Tan
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Article
| Open Access
The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination
The role that cellular bioenergetics plays in the early stages of Alzheimer’s disease is poorly understood. Here the authors describe structures of key OXPHOS assembly proteins, providing insights into how these pathways are interlinked and regulated.
- Lindsay McGregor
- , Samira Acajjaoui
- & Montserrat Soler-Lopez
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Article
| Open Access
CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection
Here the authors show that the calcium-sensing kinase CaMKK2 phosphorylates STN1 in response to replication stress and elevated cytosolic calcium concentration to protect stalled replication forks from aberrant MRE11 degradation. Cancer-associated STN1 mutations abolish STN1 phosphorylation, resulting in fork instability.
- Rishi Kumar Jaiswal
- , Kai-Hang Lei
- & Weihang Chai
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Article
| Open Access
Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation
CCAAT/enhancer binding protein α (C/EBPα) regulates myeloid differentiation, and its dysregulation contributes to acute myeloid leukaemia progress. Here the authors show that homodimer-mediated phosphorylation of C/EBPα-p42 modulates acute myeloid leukaemia cell differentiation by liquid-liquid phase separation.
- Dongmei Wang
- , Tao Sun
- & Chunyan Ji
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Article
| Open Access
A cyclin-dependent kinase-mediated phosphorylation switch of disordered protein condensation
The authors show that dynamics of protein phosphorylation in the vertebrate cell cycle is largely attributable to CDK-mediated regulation of intrinsically disordered proteins that are involved in biomolecular condensate formation.
- Juan Manuel Valverde
- , Geronimo Dubra
- & Maarten Altelaar
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Article
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A CK2 and SUMO-dependent, PML NB-involved regulatory mechanism controlling BLM ubiquitination and G-quadruplex resolution
The Bloom syndrome helicase (BLM) unwinds a variety of complex DNA structures including G quadruplex. Here the authors report RNF111-ARKL1-dependent ubiquitination of BLM in PML NBs, which limits BLM protein levels and maintains G quadruplex abundance in the nucleus.
- Shichang Liu
- , Erin Atkinson
- & Bin Wang
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Article
| Open Access
Hypoxanthine phosphoribosyl transferase 1 metabolizes temozolomide to activate AMPK for driving chemoresistance of glioblastomas
The metabolism of temozolomide (TMZ) to form methyldiazonium ions and 5-aminoimidazole-4-carboxamide (AICA) results in DNA damage, despite this, resistance frequently occurs in glioblastoma. Here, the authors demonstrate that AICA is further metabolised by HPRT1 into AICAR, which activates AMPK signalling and increases DNA damage repair. Targeting this axis in preclinical glioblastoma models sensitised tumours to TMZ.
- Jianxing Yin
- , Xiefeng Wang
- & Xu Qian
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Article
| Open Access
Ser14 phosphorylation of Bcl-xL mediates compensatory cardiac hypertrophy in male mice
The anti-apoptotic function of Bcl-xL in the heart is diminished by Mst1-mediated phosphorylation of Serine14. Here, the authors show that the Bcl-xL phosphorylation is also promoted by hemodynamic stress, which plays an essential role in mediating compensatory cardiac hypertrophy and contractility.
- Michinari Nakamura
- , Mariko Aoyagi Keller
- & Junichi Sadoshima
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Article
| Open Access
Cis P-tau is a central circulating and placental etiologic driver and therapeutic target of preeclampsia
Preeclampsia is the leading cause of maternal and fetal mortality worldwide. Here, the authors show that cis P-tau is a central circulating etiologic driver in preeclampsia and that the stereo-specific antibody targeting cis P-tau holds promise for early diagnosis and treatment of the disease.
- Sukanta Jash
- , Sayani Banerjee
- & Surendra Sharma
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Article
| Open Access
Loss of LCMT1 and biased protein phosphatase 2A heterotrimerization drive prostate cancer progression and therapy resistance
Loss of PP2A activity is often associated with cancer but the underlying mechanism remains unclear. Here, the authors show that decreased methylation of PP2A catalytic C subunit caused by loss of LCMT-1 in prostate cancer abrogates the tumor suppressor activity of PP2A on AR/MED1-dependent gene expression, proposing decreased methyl-PP2A-C as a prognostic marker for prostate cancer progression.
- Reyaz ur Rasool
- , Caitlin M. O’Connor
- & Irfan A. Asangani
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Article
| Open Access
p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1
PPARα corepressor NCoR1 is a key regulator of fatty acid β-oxidation and ketogenesis. Here, the authors demonstrate that p21-activated kinase 4 phosphorylates NCoR1 at T1619/T2124, resulting in PPARα transrepression and ketone body reduction.
- Min Yan Shi
- , Hwang Chan Yu
- & Eun Ju Bae
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Article
| Open Access
Structural insights into regulation of the PEAK3 pseudokinase scaffold by 14-3-3
PEAK pseudokinases are emerging disease targets, which regulate cell migration and proliferation through protein scaffolding. Here, the authors present the cryo-EM structure of the PEAK3/14-3-3 complex and reveal how 14-3-3 modulates PEAK3 localization and protein-protein interactions.
- Hayarpi Torosyan
- , Michael D. Paul
- & Kliment A. Verba
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Article
| Open Access
Structural mapping of PEAK pseudokinase interactions identifies 14-3-3 as a molecular switch for PEAK3 signaling
The PEAK family of pseudokinases are key hubs in cellular signalling, including cell motility and cancer. Here, the authors characterise how PEAK proteins interact with the adapter proteins CrkII and Grb2 and regulatory scaffold protein 14-3-3, to achieve functional signalling assemblies.
- Michael J. Roy
- , Minglyanna G. Surudoi
- & Isabelle S. Lucet
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Article
| Open Access
Hybrid-DIA: intelligent data acquisition integrates targeted and discovery proteomics to analyze phospho-signaling in single spheroids
Standard mass spectrometry analyses often miss key targets required for phospho-signalling reconstruction. Here, authors present an intelligent data acquisition strategy that combines discovery and targeted analysis in one run and apply it to maximize the information from single spheroids drug screenings.
- Ana Martínez-Val
- , Kyle Fort
- & Jesper V. Olsen
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Article
| Open Access
Redefining the role of AMPK in autophagy and the energy stress response
According to the current understanding in the field, AMPK promotes autophagy by activating ULK1 during energy stress. Here, authors show that AMPK is indeed a negative regulator of ULK1 and it suppresses autophagy in energy depleted cells.
- Ji-Man Park
- , Da-Hye Lee
- & Do-Hyung Kim
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Article
| Open Access
Broad phosphorylation mediated by testis-specific serine/threonine kinases contributes to spermiogenesis and male fertility
Testis-specific serine/threonine kinases have been associated with male infertility, but the mechanism for this connection is unclear. Here they identify a Drosophila homolog, dTSSK, which is essential for male fertility in fruit flies and has functionally conserved catalytic activity with human TSSKs.
- Xuedi Zhang
- , Ju Peng
- & Guanjun Gao
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Article
| Open Access
A link between STK signalling and capsular polysaccharide synthesis in Streptococcus suis
Serine/threonine kinases (STKs) regulate the synthesis of capsular polysaccharide in bacteria through unclear mechanisms. Here, Tang et al. identify a protein that is phosphorylated by an STK and modulates the activity of a phosphoregulatory system in Streptococcus suis, thus linking STKs to capsular polysaccharide synthesis.
- Jinsheng Tang
- , Mengru Guo
- & Hongjie Fan
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Article
| Open Access
Hsp90 provides a platform for kinase dephosphorylation by PP5
PP5 requires the molecular chaperone Hsp90 to dephosphorylate CRaf kinase and the Hsp90 cochaperone Cdc37. Here, authors show how Hsp90 acts as a platform to allow for targeted dephosphorylation by PP5.
- Maru Jaime-Garza
- , Carlos A. Nowotny
- & David A. Agard
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Article
| Open Access
Enhanced Ca2+-channeling complex formation at the ER-mitochondria interface underlies the pathogenesis of alcohol-associated liver disease
Ca2+ overload-induced mitochondrial dysfunction is considered a contributing factor alcohol-associated liver disease pathogenesis. Here the authors report that PDK4 promotes Ca2 + -channelling complex formation at the endoplasmic reticulum-mitochondria contact sites, which contributes to the pathogenesis of alcohol-associated liver disease in studies with male mouse and hepatocyte models.
- Themis Thoudam
- , Dipanjan Chanda
- & In-Kyu Lee
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Article
| Open Access
Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A
Tumour suppressors are inhibited in cancers and their reactivation could provide novel therapy opportunities. Here, the authors study the structural mechanism by which human tumour suppressor Protein Phosphatase 2A is inhibited in breast cancer cells by the oncoprotein CIP2A.
- Karolina Pavic
- , Nikhil Gupta
- & Jukka Westermarck
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Article
| Open Access
Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation
Brown adipose tissue (BAT) is a specialized thermogenic organ that undergoes high demands of protein synthesis during thermogenic adaptation. Here, the authors show that the cold responsive phosphatase Ssu72 is required for mRNA translation that affects thermogenic adaptation in BAT.
- Eun-Ji Park
- , Hyun-Soo Kim
- & Chang-Woo Lee
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Article
| Open Access
Protein-Peptide Turnover Profiling reveals the order of PTM addition and removal during protein maturation
Metabolic labeling is often used to measure protein turnover. Here the authors show that for interconvertible protein species like phosphoforms metabolic labeling does not provide information on turnover differences, but that the relative order of modification can determine the observed dynamics.
- Henrik M. Hammarén
- , Eva-Maria Geissen
- & Mikhail M. Savitski
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Article
| Open Access
HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation
Binding to HSP90-CDC37 is essential for the activity of many protein kinases, but its function is unclear. Here, the authors show that HSP90-CDC37 provides a structural platform for the phosphatase PP5 to dephosphorylate a bound kinase, ‘factory resetting’ it prior to release.
- Jasmeen Oberoi
- , Xavi Aran Guiu
- & Laurence H. Pearl
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Article
| Open Access
Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance
Immune checkpoint blockade is showing promise in cancer immune therapy, but many solid tumours are resistant. Authors here identify a pathway in T cells that leads to increased activity of C-terminal Src kinase, a negative regulator of T cell activity, thus disabling tumour infiltrating T cells and causing immune therapy resistance.
- Dhivya Sridaran
- , Surbhi Chouhan
- & Nupam P. Mahajan
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Article
| Open Access
An mTORC1-mediated negative feedback loop constrains amino acid-induced FLCN-Rag activation in renal cells with TSC2 loss
The MiT/TFE transcription factors are phosphorylated and inactivated by mTORC1. Here, authors demonstrate that TFEB is paradoxically hypophosphorylated and activated in cells with TSC2 loss due to impaired lysosomal recruitment of the FLCN:FNIP2 complex in renal cells.
- Kaushal Asrani
- , Juhyung Woo
- & Tamara L. Lotan
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Article
| Open Access
CK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site
Here the authors identify SUZ12 as a cellular substate of casein kinase 2 (CK2), and show this phosphorylation changes the active site structure of Polycomb repressive complex 2 (PRC2) and promotes PRC2 function in cell identity maintenance during stem cell differentiation.
- Lihu Gong
- , Xiuli Liu
- & Xin Liu
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Article
| Open Access
Spatially resolved phosphoproteomics reveals fibroblast growth factor receptor recycling-driven regulation of autophagy and survival
Recruitment of Receptor Tyrosine Kinase signalling partners during endocytosis, specifically during recycling to the plasma membrane, is crucial to signal propagation and regulation. Here, the authors reveal FGFR signalling partners proximal to recycling endosomes with a spatially resolved phosphoproteomics approach.
- Joanne Watson
- , Harriet R. Ferguson
- & Chiara Francavilla
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Article
| Open Access
NIMA-related kinase 9 regulates the phosphorylation of the essential myosin light chain in the heart
Phosphorylation of the essential myosin light chain (ELC) influence actin-myosin crossbridge cycling in the heart. Here, the authors show upregulated ELC-phosphorylation in systolic heart failure and identify NIMArelated kinase 9 to bind to ELC mediating its calcium-dependent phosphorylation.
- Marion Müller
- , Rose Eghbalian
- & Benjamin Meder
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Article
| Open Access
An intrinsic temporal order of c-JUN N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment
Phosphorylation at multiple sites is a major regulatory mechanism in cellular signalling. Here, the authors show that multisite phosphorylation of the c-JUN transcription factor by the JNK kinase exhibits intrinsic kinetics that allow a precise and timed regulation of the transcriptional output.
- Christopher A. Waudby
- , Saul Alvarez-Teijeiro
- & Anastasia Mylona
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Article
| Open Access
Aschoff’s rule on circadian rhythms orchestrated by blue light sensor CRY2 and clock component PRR9
Circadian pace is modulated by light intensity. Here the authors show that CRY2 interacts with PRR9 to mediate blue light input to the circadian clock and is degraded at higher light intensity offering a mechanistic explanation as to how intensity can modify clock place.
- Yuqing He
- , Yingjun Yu
- & Lei Wang
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Article
| Open Access
MYPT1-PP1β phosphatase negatively regulates both chromatin landscape and co-activator recruitment for beige adipogenesis
How β-AR signaling coordinates epigenetic and transcriptional pathways is unknown. Here the authors show that cold-induced β-AR signaling negatively regulates MYPT1-PP1β phosphatase activity to orchestrate both pathways for beige adipogenesis.
- Hiroki Takahashi
- , Ge Yang
- & Juro Sakai
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Article
| Open Access
Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling
SHP2 is an important human tyrosine phosphatase with key roles in cancer, immune responses and insulin signaling. Here, the authors explore its substrate recognition mechanism in molecular detail and uncover a complex regulatory mechanism for this enzyme that marks specific target sites for dephosphorylation.
- András Zeke
- , Tamás Takács
- & Attila Reményi
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Article
| Open Access
Transcription-independent regulation of STING activation and innate immune responses by IRF8 in monocytes
The transcription factor IRF8 has been shown to regulate monocyte differentiation via its DNA-binding activity. Here authors show that IRF8 is also involved in cytosolic DNA sensing via its phosphorylation-dependent association to the adaptor protein STING, thus representing an important checkpoint between immune response and autoimmunity in monocytes.
- Wei-Wei Luo
- , Zhen Tong
- & Yan-Yi Wang
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Article
| Open Access
CDC-like kinase 4 deficiency contributes to pathological cardiac hypertrophy by modulating NEXN phosphorylation
Phosphorylation catalyzed by kinases is a key event in signaling pathways involved in cardiomyocyte hypertrophy. Here the authors show that the kinase CLK4 ameliorates cardiac hypertrophy by phosphorylating NEXN.
- Jian Huang
- , Luxin Wang
- & Yi-Han Chen
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Article
| Open Access
KSTAR: An algorithm to predict patient-specific kinase activities from phosphoproteomic data
Kinases are important drug targets, but predicting their activities from phosphoproteomics data remains challenging. While many existing prediction tools rely on phosphosite-specific quantitative data, Crowl et al. develop a kinase activity prediction algorithm that requires no phosphosite quantification.
- Sam Crowl
- , Ben T. Jordan
- & Kristen M. Naegle
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Article
| Open Access
Allosteric inhibition of PPM1D serine/threonine phosphatase via an altered conformational state
In this work, the authors report a sophisticated combination of genetic, biophysical, and biochemical analyses to identifies the cycling conformational states of PPM1D. The findings reveal how an allosteric inhibitor locks the protein into a conformationally inactive state, and explain the distribution of PPM1D activating mutations in cancer.
- Peter G. Miller
- , Murugappan Sathappa
- & Benjamin L. Ebert
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Article
| Open Access
EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation
Breast cancer cells are known to metastasize to the bone but why the cells should migrate and metastasize to this particular organ is not clearly understood. Here, the authors show that EZH2 activates an integrin B1 and FAK signaling pathway in breast cancer cells, which activates TGFB signaling to drive metastasis in the bone.
- Lin Zhang
- , Jingkun Qu
- & Dihua Yu
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Article
| Open Access
Robust and tunable signal processing in mammalian cells via engineered covalent modification cycles
Phosphorylation networks are frequently at the heart of complex cellular decision making. Here the authors engineer synthetic phosphorylation devices with feedback regulation in mammalian cells and demonstrate how to use these to achieve tunable and robust control of cell behaviours.
- Ross D. Jones
- , Yili Qian
- & Ron Weiss
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Article
| Open Access
Siwi cooperates with Par-1 kinase to resolve the autoinhibitory effect of Papi for Siwi-piRISC biogenesis
Siwi-piRISC protects the germline genome from DNA damage caused by selfish movement of transposons by suppressing their expression. Here, the authors show how molecularly Papi, which plays an important role in the production of Siwi-piRISC, cooperates with Par-1 kinase to ensure the accumulation of Siwi-piRISC in germ cells.
- Hiromi Yamada
- , Kazumichi M. Nishida
- & Mikiko C. Siomi
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Article
| Open Access
GPCR kinase knockout cells reveal the impact of individual GRKs on arrestin binding and GPCR regulation
GPCR kinases (GRKs) regulate GPCR interactions and thus functions. Here, the authors report a comprehensive panel of GRK knockout cells, used to assess the GRK-specific β-arrestin recruitment. Selective engagement of GRKs induces distinct GPCR–β-arrestin complexes.
- J. Drube
- , R. S. Haider
- & C. Hoffmann
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Article
| Open Access
The catalytic activity of TCPTP is auto-regulated by its intrinsically disordered tail and activated by Integrin alpha-1
TCPTP is a non-receptor type protein tyrosine phosphatase involved in various signalling pathways. Here, the authors provide structural insights into TCPTP activation, showing that TCPTP is inhibited by its C-terminal tail, which can be displaced by the cytosolic tail of integrin-α1, leading to activation.
- Jai Prakash Singh
- , Yang Li
- & Tzu-Ching Meng
OsMAPK6 phosphorylation and CLG1 ubiquitylation of GW6a non-additively enhance rice grain size through stabilization of the substrate