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PMID:28428613

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Citation

Cobbaut, M, Derua, R, Döppler, H, Lou, HJ, Vandoninck, S, Storz, P, Turk, BE, Seufferlein, T, Waelkens, E, Janssens, V and Van Lint, J (2017) Differential regulation of PKD isoforms in oxidative stress conditions through phosphorylation of a conserved Tyr in the P+1 loop. Sci Rep 7:887

Abstract

Protein kinases are essential molecules in life and their crucial function requires tight regulation. Many kinases are regulated via phosphorylation within their activation loop. This loop is embedded in the activation segment, which additionally contains the Mg binding loop and a P + 1 loop that is important in substrate binding. In this report, we identify Abl-mediated phosphorylation of a highly conserved Tyr residue in the P + 1 loop of protein kinase D2 (PKD2) during oxidative stress. Remarkably, we observed that the three human PKD isoforms display very different degrees of P + 1 loop Tyr phosphorylation and we identify one of the molecular determinants for this divergence. This is paralleled by a different activation mechanism of PKD1 and PKD2 during oxidative stress. Tyr phosphorylation in the P + 1 loop of PKD2 increases turnover for Syntide-2, while substrate specificity and the role of PKD2 in NF-κB signaling remain unaffected. Importantly, Tyr to Phe substitution renders the kinase inactive, jeopardizing its use as a non-phosphorylatable mutant. Since large-scale proteomics studies identified P + 1 loop Tyr phosphorylation in more than 70 Ser/Thr kinases in multiple conditions, our results do not only demonstrate differential regulation/function of PKD isoforms under oxidative stress, but also have implications for kinase regulation in general.

Links

PubMed PMC5430542 Online version:10.1038/s41598-017-00800-w

Keywords

Conserved Sequence; HEK293 Cells; HeLa Cells; Humans; Isoenzymes/chemistry; Isoenzymes/genetics; Isoenzymes/metabolism; NF-kappa B/metabolism; Oxidative Stress; Peptides/metabolism; Phosphorylation; Protein Domains; Protein Kinase C/chemistry; Protein Kinase C/genetics; Protein Kinase C/metabolism; Protein Processing, Post-Translational; Tyrosine/genetics; Tyrosine/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ABL1

involved_in

GO:0018108: peptidyl-tyrosine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q9BZL6)

Seeded From UniProt

complete

HUMAN:ABL1

enables

GO:0004715: non-membrane spanning protein tyrosine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ABL1

involved_in

GO:0018108: peptidyl-tyrosine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

has_regulation_target:(UniProtKB:Q9BZL6)

Seeded From UniProt

complete

HUMAN:KPCD2

enables

GO:0005080: protein kinase C binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q05655

F

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

GO:0018107: peptidyl-threonine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

GO:0018105: peptidyl-serine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KPCD2

involved_in

GO:0051092: positive regulation of NF-kappaB transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KPCD2

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0018107: peptidyl-threonine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KPCD1

involved_in

GO:0018105: peptidyl-serine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KPCD1

enables

GO:0004674: protein serine/threonine kinase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:KPCD

enables

GO:0019901: protein kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BZL6

F

Seeded From UniProt

complete

Notes

See also

References

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