PhosphoPOINT: a comprehensive human kinase interactome and phospho-protein database

Yang, Chia Ying; Chang, Chao-Hui; Yu, Ya Ling; Lin, Tsu Chun Emma; Lee, Sheng An; Yen, Chueh Chuan; Yang, Jiawei; Lai, Jin Mei; Hong, Yi‐Ren; Tseng, Tzu Ling; Chao, Kun-Mao; Huang, Chi Ying F.

doi:10.1093/bioinformatics/btn297

Cited by 92 publications

(79 citation statements)

References 37 publications

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“…The physical networks are based upon binding data (e.g. yeast two hybrid, co‐immunoprecipitation) for the C. elegans kinase and/or data for the yeast, fly, rodent, and/or human orthologue35, 36, 37 while the functional networks are based upon limited genetic interactions for the C. elegans kinase and/or data for the yeast, fly, rodent, and/or human orthologue35, 36, 37 and a large amount of biochemical data for shared interacting phospho‐proteins for the human orthologue 27. Visualization of these predicted interactions using cytoscape did indeed reveal some potential interaction networks (see Supporting Information [Link], [Link]).…”

Section: Resultsmentioning

confidence: 99%

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Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Lehmann

Bass

Barratt

et al. 2017

J cachexia sarcopenia muscle

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BackgroundSkeletal muscle is central to locomotion and metabolic homeostasis. The laboratory worm Caenorhabditis elegans has been developed into a genomic model for assessing the genes and signals that regulate muscle development and protein degradation. Past work has identified a receptor tyrosine kinase signalling network that combinatorially controls autophagy, nerve signal to muscle to oppose proteasome‐based degradation, and extracellular matrix‐based signals that control calpain and caspase activation. The last two discoveries were enabled by following up results from a functional genomic screen of known regulators of muscle. Recently, a screen of the kinome requirement for muscle homeostasis identified roughly 40% of kinases as required for C. elegans muscle health; 80 have identified human orthologues and 53 are known to be expressed in skeletal muscle. To complement this kinome screen, here, we screen most of the phosphatases in C. elegans . MethodsRNA interference was used to knockdown phosphatase‐encoding genes. Knockdown was first conducted during development with positive results also knocked down only in fully developed adult muscle. Protein homeostasis, mitochondrial structure, and sarcomere structure were assessed using transgenic reporter proteins. Genes identified as being required to prevent protein degradation were also knocked down in conditions that blocked proteasome or autophagic degradation. Genes identified as being required to prevent autophagic degradation were also assessed for autophagic vesicle accumulation using another transgenic reporter. Lastly, bioinformatics were used to look for overlap between kinases and phosphatases required for muscle homeostasis, and the prediction that one phosphatase was required to prevent mitogen‐activated protein kinase activation was assessed by western blot.ResultsA little over half of all phosphatases are each required to prevent abnormal development or maintenance of muscle. Eighty‐six of these phosphatases have known human orthologues, 57 of which are known to be expressed in human skeletal muscle. Of the phosphatases required to prevent abnormal muscle protein degradation, roughly half are required to prevent increased autophagy.ConclusionsA significant portion of both the kinome and phosphatome are required for establishing and maintaining C. elegans muscle health. Autophagy appears to be the most commonly triggered form of protein degradation in response to disruption of phosphorylation‐based signalling. The results from these screens provide measurable phenotypes for analysing the combined contribution of kinases and phosphatases in a multi‐cellular organism and suggest new potential regulators of human skeletal muscle for further analysis.

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Section: Resultsmentioning

confidence: 99%

“…(A) Kinases and phosphatases that were identified as required for lack of pathological protein degradation in muscle were examined for functional interactions in WormBase,22 GeneMANIA,26 and PhosphoPOINT 27. Kinases are indicated in blue and phosphatases in yellow.…”

Section: Resultsmentioning

confidence: 99%

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Lehmann

Bass

Barratt

et al. 2017

J cachexia sarcopenia muscle

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“…The network used to simulate lung cells was built by combining the kinase interactome from Phospho-POINT [32] with the transcription factor interactome from TRANSFAC [33]. Both of these are general networks that were constructed by compiling many observed pairwise interactions between components, meaning that if j !…”

Section: A Lung Cell Networkmentioning

confidence: 99%

“…We will use two di↵erent networks for this analysis. The first is an experimentally validated and nonspecific network obtained from a kinase interactome and phospho-protein database [32] combined with a database of interactions between transcription factors and their target genes [33]. The second network is cell-specific and was obtained using network reconstruction algorithms and transcriptional and post-translational data from mature human B cells [34].…”

Section: Introductionmentioning

confidence: 99%

Attractor Signaling Models for Discovery of Combinatorial Therapies

Piermarocchi¹

2013

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE 2. REPORT TYPE Annual DATES COVERED (From -To) TITLE AND SUBTITLEAttractor ignaling odels for iscovery of mbinatorial herapies 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER AUTHOR(S)Carlo Piermarocchi 5d. PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Michigan State University AND ADDRESS(ES) Easy PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) SPONSOR/MONITOR'S ACRONYM(S) SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release SUPPLEMENTARY NOTES ABSTRACTThe objective of this project consists in demonstrating that attractor models increase the chances of discovering combinations of many drugs with strong synergistic effects in lung cancer. The approach will be tested using a high throughput screening facility to compare the therapeutic effectiveness of random combinations and combinations predicted to be effective by the model. !Drug-based!therapies!are!therefore!the! best!option,!but!intrinsic!and!acquired!drug!resistance!still!makes!the!5-year!survival!rate!for!this!disease! less!than!15%.!Over!the!years,!many!specific!mechanisms!associated!with!drug!resistance!in!lung!cancer! have! been! pinpointed,! but! we! are! still! far! from! understanding! how! to! overcome! it. Combination! drug! therapy!is!commonly!used!to!enhance!efficacy!and!overcome!drug!resistance!in!cancer,!but!at!present! the! choice! of! drugs! and! doses! is! based! on! empirical! clinical! experience! alone.! In! this! project! we! have! used! an! interdisciplinary! approach! based! on! the! mathematics! of! complex! networks! to! identify! drug! combinations!that!could!be!effective!in!the!therapy!of!lung!cancer.!! ! This! reports! describes! the! methods! used! and! presents! some! preliminary! computational! and! experimental! data! that! we! have! obtained! during! the! first! year! of! operations.! The! project! has! been! extended!to!August!14!2014!and!additional!details!and!data!will!be!included!in!the!final!report.! ! ! ! where!! !" !is!the!adjacency!matrix!of!the!lu...

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“…We use two different networks for this analysis. The first is an experimentally validated and non-specific network (that is, the observed interactions are compiled from many experiments conducted on heterogeneous cell types) obtained from a kinase interactome and phospho-protein database [32] combined with a database of interactions between transcription factors and their target genes [33]. The second network is cellspecific and was obtained using network reconstruction algorithms and transcriptional and post-translational data from mature human B cells [34].…”

Section: Introductionmentioning

confidence: 99%

Attractor Signaling Models for Discovery of Combinatorial Therapies

Piermarocchi¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATENovember PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)Michigan State University Easy Lansing, MI 48824 AND ADDRESS(ES) Easy PERFORMING ORGANIZATION REPORT NUMBER SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for public release SUPPLEMENTARY NOTES 2 ABSTRACTThe objective of this project consists in demonstrating that attractor models increase the chances of discovering combinations of many drugs with strong synergistic effects in lung cancer. The approach will be tested using a high throughput screening facility to compare the therapeutic effectiveness of random combinations and combinations predicted to be effective by the model. Final Report! Grant:!W81XWH-12-1-0233!! PI:!Carlo!Piermarocchi!Michigan!State!University! Title:!Attractor!signaling!models!for!discovery!of!combinatorial!therapies! Total!period!of!performance:!Aug!15!2012-!Aug!14!2014! ! ! Introduction! ! Surgery!and!radiation!therapies!are!difficult!to!use!in!the!treatment!of!lung!cancer!because!the! diagnosis!often!occurs!when!patients!already!have!metastasis.!Drug-based!therapies!are!therefore!the! best!option,!but!intrinsic!and!acquired!drug!resistance!still!makes!the!5-year!survival!rate!for!this!disease! less!than!15%.!Over!the!years,!many!specific!mechanisms!associated!with!drug!resistance!in!lung!cancer! have! been! pinpointed,! but! we! are! still! far! from! understanding! how! to! overcome! it. Combination! drug! therapy!is!commonly!used!to!enhance!efficacy!and!overcome!drug!resistance!in!cancer,!but!at!present! the! choice! of! drugs! and! doses! is! based! on! empirical! clinical! experience! alone.! In! this! project! we! have! used! an! interdisciplinary! approach! based! on! the! mathematics! of! complex! networks! to! identify! drug! combinations!that!could!be!effective!in!the!therapy!of!lung!cancer.!! ! This! reports! describes! the! methods! used! and! presents! computational! and! experimental! data! that!we!have!obtained!...

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PhosphoPOINT: a comprehensive human kinase interactome and phospho-protein database

Abstract: Supplementary data are available at Bioinformatics online.

Cited by 92 publications

References 37 publications

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Attractor Signaling Models for Discovery of Combinatorial Therapies

Attractor Signaling Models for Discovery of Combinatorial Therapies

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