Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases

Buljan, Marija; Ciuffa, Rodolfo; Drogen, Audrey van; Vichalkovski, Anton; Mehnert, Martin; Rosenberger, George; Lee, Sohyon; Varjosalo, Markku; Pernas, Lucia Espona; Spegg, Vincent; Snijder, Berend; Aebersold, Ruedi; Gstaiger, Matthias

doi:10.1016/j.molcel.2020.07.001

Cited by 96 publications

(96 citation statements)

References 107 publications

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“…In further support of these interrelations, the number of 14-3-3 prey-binding baits also indicated correlation with the affinity trend of 14-3-3 isoforms when using data from a recent independent study ( https://sec-explorer.shinyapps.io/Kinome_interactions/ and 49 ) that used AP-MS to uncover the interactions of more than 300 protein kinases ( R 2 = 0.64) (Supplementary Fig. 7a ).…”

Section: Resultsmentioning

confidence: 62%

“…Conversely, the seven 14-3-3 isoforms bound each E6 phosphopeptide following a conserved hierarchized profile, with an approximate 11-fold K D ratio between the strongest-binding and the weakest-binding 14-3-3 isoform. Remarkably, 14-3-3 proteins obey the same hierarchy when binding to most of their targets, as supported by our own data on RSK1 and HSPB6 peptides, by our literature curation 40 , 44 – 48 , and by the unbiased proteome-wide complexome datasets such as the BioPlex 3 database ( https://bioplex.hms.harvard.edu and 29 ) or the human kinome interactome ( https://sec-explorer.shinyapps.io/Kinome_interactions/ and 49 ). Only 14-3-3σ may stand out as a partial exception to this rule.…”

Section: Discussionmentioning

confidence: 61%

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Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms

et al. 2021

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The seven 14-3-3 isoforms are highly abundant human proteins encoded by similar yet distinct genes. 14-3-3 proteins recognize phosphorylated motifs within numerous human and viral proteins. Here, we analyze by X-ray crystallography, fluorescence polarization, mutagenesis and fusicoccin-mediated modulation the structural basis and druggability of 14-3-3 binding to four E6 oncoproteins of tumorigenic human papillomaviruses. 14-3-3 isoforms bind variant and mutated phospho-motifs of E6 and unrelated protein RSK1 with different affinities, albeit following an ordered affinity ranking with conserved relative KD ratios. Remarkably, 14-3-3 isoforms obey the same hierarchy when binding to most of their established targets, as supported by literature and a recent human complexome map. This knowledge allows predicting proportions of 14-3-3 isoforms engaged with phosphoproteins in various tissues. Notwithstanding their individual functions, cellular concentrations of 14-3-3 may be collectively adjusted to buffer the strongest phosphorylation outbursts, explaining their expression variations in different tissues and tumors.

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Section: Resultsmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 61%

Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms

et al. 2021

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“…Among the effective combinations identified from this screen, we found that a novel combination, pairing the CK2 inhibitor CX-4945 with the ATM inhibitor KU-60019, dramatically enhanced cell death in VHL-deficient renal carcinoma cells. CK2 has effects on a broad range of cellular functions participating to the (DDR) [ 98 ] and to the regulation of chromatin modifiers [ 99 , 100 , 101 , 102 , 103 ]. More specifically, its implication in tumor development and recurrence may be related to its double-edge functions in promoting cell growth and inhibiting apoptotic cell death [ 104 ] and in the development of multidrug resistance phenotypes [ 35 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

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Séraudie

et al. 2021

Cancers

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Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL− cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug–gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC.

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“…The advances in high‐accuracy mass spectrometry has led proteomics to be a powerful tool for unveiling complex protein network in cells 47 . Researchers generally use the total proteome or phospho‐proteome to extract disease‐related protein networks, such as explored here for EGFR‐mutant NSCLC 48,49 . Recently, Nishimura et al analyzed 36 FFPE tissues of lung adenocarcinomas using semi‐quantitative shotgun proteomics.…”

Section: Discussionmentioning

confidence: 99%

N‐glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC

et al. 2021

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Lung cancer is the leading cause of cancer‐related death worldwide. As well as the identified role of epidermal growth factor receptor (EGFR), its association with driver mutations has improved the therapeutics for patients with lung cancer harboring EGFR mutations. These patients usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying the wild‐type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. Expression of transmembrane glycoprotein non‐metastatic melanoma protein B (GPNMB) was positively correlated with the status of mutated EGFR in non‐small‐cell lung cancer (NSCLC). This protein was not only overexpressed but also highly glycosylated in EGFR‐mutated, especially EGFR‐L858R mutated, NSCLC cells. Further examination showed that GPNMB could activate mutated EGFR without ligand stimulation and could bind to the C‐terminus of EGFR, assist phosphorylation at Y845, turn on downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that Asn134 (N134) glycosylation of GPNMB played a crucial role in this ligand‐independent regulation. Depleting N134‐glycosylation on GPNMB could dramatically inhibit binding of GPNMB to mutated EGFR, blocking its downstream signaling, and ultimately inhibiting cancer metastasis in NSCLC. Clarifying the role of N‐glycosylated GPNMB in regulating the ligand‐independent activation of mutated EGFR may soon give new insight into the development of novel therapeutics for NSCLC.

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Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases

Cited by 96 publications

References 107 publications

Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms

Hierarchized phosphotarget binding by the seven human 14-3-3 isoforms

Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction

N‐glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC

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