Abstract：
:Phosphorylation networks intimately regulate mechanisms of response to therapies. Mapping the phospho-catalytic profile of kinases in cells or tissues remains a challenge. Here, we introduce a practical high-throughput system to measure the enzymatic activity of kinases using biological peptide targets as phospho-sensors to reveal kinase dependencies in tumour biopsies and cell lines. A 228-peptide screen was developed to detect the activity of >60 kinases, including ABLs, AKTs, CDKs and MAPKs. Focusing on BRAFV600E tumours, we found mechanisms of intrinsic resistance to BRAFV600E-targeted therapy in colorectal cancer, including targetable parallel activation of PDPK1 and PRKCA. Furthermore, mapping the phospho-catalytic signatures of melanoma specimens identifies RPS6KB1 and PIM1 as emerging druggable vulnerabilities predictive of poor outcome in BRAFV600E patients. The results show that therapeutic resistance can be caused by the concerted upregulation of interdependent pathways. Our kinase activity-mapping system is a versatile strategy that innovates the exploration of actionable kinases for precision medicine.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Coppé JP,Mori M,Pan B,Yau C,Wolf DM,Ruiz-Saenz A,Brunen D,Prahallad A,Cornelissen-Steijger P,Kemper K,Posch C,Wang C,Dreyer CA,Krijgsman O,Lee PRE,Chen Z,Peeper DS,Moasser MM,Bernards R,van 't Veer LJdoi
10.1038/s41556-019-0328-zsubject
Has Abstractpub_date
2019-06-01 00:00:00pages
778-790issue
6eissn
1465-7392issn
1476-4679pii
10.1038/s41556-019-0328-zjournal_volume
21pub_type
杂志文章abstract：:The contribution of autophagy to cancer development remains controversial, largely owing to the fact that autophagy can be tumour suppressive or oncogenic in different biological contexts. Here, we show that in non-small-cell lung cancer (NSCLC), casein kinase 1 alpha 1 (CK1α) suppresses tumour growth by functioning a...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/s41556-018-0065-8
更新日期：2018-04-01 00:00:00
abstract：:Telomere attrition and other forms of telomere damage can activate the ATM kinase pathway. What generates the DNA damage signal at mammalian chromosome ends or at other double-strand breaks is not known. Telomere dysfunction is often accompanied by disappearance of the 3' telomeric overhang, raising the possibility th...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1275
更新日期：2005-07-01 00:00:00
abstract：:In response to DNA damage, eukaryotic cells use a system of checkpoint controls to delay cell-cycle progression. Checkpoint delays provide time for repair of damaged DNA before its replication in S phase and before segregation of chromatids in M phase. The Cds1 (Chk2) tumour-suppressor protein has been implicated in c...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/35036406
更新日期：2000-10-01 00:00:00
abstract：:The planar cell polarity (PCP) signalling pathway is essential for embryonic development because it governs diverse cellular behaviours, and 'core PCP' proteins, such as Dishevelled and Frizzled, have been extensively characterized. By contrast, the 'PCP effector' proteins, such as Intu and Fuz, remain largely unstudi...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1966
更新日期：2009-10-01 00:00:00
abstract：:Extracellular signal regulated kinases (ERKs) represent a signalling hub in many physiological responses and have pivotal functions in cell proliferation, differentiation, development and death, as well as in synaptic plasticity. Mitogen-activated protein kinase phosphatases (MKPs) selectively inactivate ERKs by depho...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1447
更新日期：2006-08-01 00:00:00
abstract：:Humans suffer from high rates of fetal aneuploidy, often arising from the absence of meiotic crossover recombination between homologous chromosomes. Meiotic recombination is initiated by double-strand breaks (DSBs) generated by the SPO11 transesterase. In yeast and worms, at least one buffering mechanism, crossover ho...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb2451
更新日期：2012-03-04 00:00:00
abstract：:Mammalian and most fungal infectious proteins (also known as prions) are self-propagating amyloid, a filamentous beta-sheet structure. A prion domain determines the infectious properties of a protein by forming the core of the amyloid. We compare the properties of known prion domains and their interactions with the re...
journal_title：Nature cell biology
pub_type： 杂志文章,评审
doi：10.1038/ncb1105-1039
更新日期：2005-11-01 00:00:00
abstract：:Innovations in live-cell microscopy and single-molecule analysis have allowed a new direct view of nuclear messenger RNA dynamics. A new study extends previous analyses of mRNA-protein intranuclear transport and links this critical step to the kinetics of moving through nuclear pore complexes. Seeing nuclear mRNA on t...
journal_title：Nature cell biology
pub_type： 评论,杂志文章
doi：10.1038/ncb0610-525
更新日期：2010-06-01 00:00:00
abstract：:During the development of multicellular organisms, concerted actions of molecular signalling networks determine whether cells undergo proliferation, differentiation, death or ageing. Here we show that genetic inactivation of the stress signalling kinase, MKK7, a direct activator of JNKs in mice, results in embryonic l...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1098
更新日期：2004-03-01 00:00:00
abstract：:Cellular transformation and cancer progression is accompanied by changes in the metabolic landscape. Master co-regulators of metabolism orchestrate the modulation of multiple metabolic pathways through transcriptional programs, and hence constitute a probabilistically parsimonious mechanism for general metabolic rewir...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb3357
更新日期：2016-06-01 00:00:00
abstract：:Actomyosin contractility is a mechanism by which cells exert locomotory force against their environment. Signalling downstream of the small GTPase Rho increases contractility through Rho-kinase (ROCK)-mediated regulation of myosin-II light chain (MLC2) phosphorylation. Cdc42 signalling has been shown to control cell p...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1230
更新日期：2005-03-01 00:00:00
abstract：:Gastrulation leads to three germ layers--ectoderm, mesoderm and endoderm--that are separated by two basement membranes. In the mouse embryo, the emergent gut endoderm results from the widespread intercalation of cells of two distinct origins: pluripotent epiblast-derived definitive endoderm (DE) and extra-embryonic vi...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb3070
更新日期：2014-12-01 00:00:00
abstract：:Repulsive guidance molecule (RGM) is a recently identified protein implicated in both axonal guidance and neural tube closure. The avoidance of chick RGM in the posterior optic tectum by growing temporal, but not nasal, retinal ganglion cell axons is thought to contribute to visual map formation. In contrast to ephrin...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1156
更新日期：2004-08-01 00:00:00
abstract：:The vertebrate neural crest arises at the border of the neural plate during early stages of nervous system development; however, little is known about the molecular mechanisms underlying neural crest formation. Here we identify a secreted protein, Noelin-1, which has the ability to prolong neural crest production. Noe...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/35008643
更新日期：2000-04-01 00:00:00
abstract：:The deposition of chemical modifications into RNA is a crucial regulator of temporal and spatial gene expression programs during development. Accordingly, altered RNA modification patterns are widely linked to developmental diseases. Recently, the dysregulation of RNA modification pathways also emerged as a contributo...
journal_title：Nature cell biology
pub_type： 杂志文章,评审
doi：10.1038/s41556-019-0319-0
更新日期：2019-05-01 00:00:00
abstract：:The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cel...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb3195
更新日期：2015-08-01 00:00:00
abstract：:Aurora A, an integral mitotic kinase, is essential for microtubule dynamics of post-mitotic neurons. PKCzeta activates Aurora A, which in turn phosphorylates NDEL1 to promote neurite extension. This raises the possibility that Aurora A may also be involved in establishing cell polarity and axon/dendrite elaboration in...
journal_title：Nature cell biology
pub_type： 评论,新闻
doi：10.1038/ncb0909-1053
更新日期：2009-09-01 00:00:00
abstract：:Secretory proteins are transported to the Golgi complex in vesicles that bud from the endoplasmic reticulum. The cytoplasmic coat protein complex II (COPII) is responsible for cargo sorting and vesicle morphogenesis. COPII was first described in Saccharomyces cerevisiae, but its basic function is conserved throughout ...
journal_title：Nature cell biology
pub_type： 杂志文章,评审
doi：10.1038/ncb2390
更新日期：2011-12-22 00:00:00
abstract：:Canonical Wnt signalling has been implicated in mouse and human embryonic stem cell (ESC) maintenance; however, its requirement is controversial. β-catenin is the key component in this highly conserved Wnt pathway, acting as a transcriptional transactivator. However, β-catenin has additional roles at the plasma membra...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb2260
更新日期：2011-06-19 00:00:00
abstract：:Metaphase spindles are microtubule-based structures that use a multitude of proteins to modulate their morphology and function. Today, we understand many details of microtubule assembly, the role of microtubule-associated proteins, and the action of molecular motors. Ultimately, the challenge remains to understand how...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb2834
更新日期：2013-09-01 00:00:00
abstract：:Adenomatous polyposis coli protein (APC) is an important tumour suppressor in the human colon epithelium. In a complex with glycogen synthase kinase-3 (GSK-3), APC binds to and destabilizes cytoplasmic ('free') beta-catenin. Here, using a yeast two-hybrid screen for proteins that bind to the Drosophila beta-catenin ho...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/11064
更新日期：1999-07-01 00:00:00
abstract：:A number of key regulators of mouse embryonic stem (ES) cell identity, including the transcription factor Nanog, show strong expression fluctuations at the single-cell level. The molecular basis for these fluctuations is unknown. Here we used a genetic complementation strategy to investigate expression changes during ...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb2603
更新日期：2012-11-01 00:00:00
abstract：:Focal adhesions are integrin-based multiprotein complexes, several micrometres in diameter, that mechanically link the extracellular matrix with the termini of actin bundles. The molecular diversity of focal adhesions and their role in cell migration and matrix sensing has been extensively studied, but their ultrastru...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb2095
更新日期：2010-09-01 00:00:00
abstract：:Protein kinases have central functions in various cellular signal transduction pathways through their substrate phosphorylation. Here we show that a protein kinase, DYRK2, has unexpected role as a scaffold for an E3 ubiquitin ligase complex. DYRK2 associates with an E3 ligase complex containing EDD, DDB1 and VPRBP pro...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1848
更新日期：2009-04-01 00:00:00
abstract：:Hippo signalling has been associated with many important tissue functions including the regulation of organ size. In the intestinal epithelium differing functions have been proposed for the effectors of Hippo signalling, YAP and TAZ1. These are now shown to have a dual role in the intestinal epithelium, regulating bot...
journal_title：Nature cell biology
pub_type： 评论,杂志文章
doi：10.1038/ncb3086
更新日期：2015-01-01 00:00:00
abstract：:Transforming growth factor-beta (TGF-beta) induces epithelial-mesenchymal transdifferentiation (EMT) accompanied by cellular differentiation and migration. Despite extensive transcriptomic profiling, the identification of TGF-beta-inducible, EMT-specific genes has met with limited success. Here we identify a post-tran...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb2029
更新日期：2010-03-01 00:00:00
abstract：:Metastatic cancer is a systemic disease, and metastasis determinants might elicit completely different effects in various target organs. Here we show that tumour-secreted DKK1 is a serological marker of breast cancer metastasis organotropism and inhibits lung metastasis. DKK1 suppresses PTGS2-induced macrophage and ne...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb3613
更新日期：2017-10-01 00:00:00
abstract：:Proteins containing ubiquitin-binding domains (UBDs) interact with ubiquitinated targets and regulate diverse biological processes, including endocytosis, signal transduction, transcription and DNA repair. Many of the UBD-containing proteins are also themselves monoubiquitinated, but the functional role and the mechan...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1354
更新日期：2006-02-01 00:00:00
abstract：:Localization and activation of heterotrimeric G proteins have a crucial role during asymmetric cell division. The asymmetric division of the Drosophila sensory precursor cell (pl) is polarized along the antero-posterior axis by Frizzled signalling and, during this division, activation of Galphai depends on Partner of ...
journal_title：Nature cell biology
pub_type： 杂志文章
doi：10.1038/ncb1319
更新日期：2005-11-01 00:00:00
abstract：:Inactivation of the von Hippel-Lindau (VHL) tumour-suppressor protein (pVHL) is associated with the von Hippel-Lindau cancer syndrome and the majority of kidney cancers. New evidence suggests that pVHL has properties of an F-box protein that targets the alpha-subunits of hypoxia-inducible factor (HIF)-1 for oxygen-dep...
journal_title：Nature cell biology
pub_type： 评论,新闻
doi：10.1038/35017129
更新日期：2000-07-01 00:00:00
