Phosphorylation of JAK2 at serine 523: a negative regulator of JAK2 that is stimulated by growth hormone and epidermal growth factor.
The tyrosine kinase JAK2 is a key signaling protein for at least 20 receptors in the cytokine/hematopoietin receptor superfamily and is a component of signaling for multiple receptor tyrosine kinases and several G-protein-coupled receptors. In this study, phosphopeptide affinity enrichment and mass spectrometry identified serine 523 (Ser523) in JAK2 as a site of phosphorylation. A phosphoserine 523 antibody revealed that Ser523 is rapidly but transiently phosphorylated in response to growth hormone (GH). MEK1 inhibitor UO126 suppresses GH-dependent phosphorylation of Ser523, suggesting that extracellular signal-regulated kinases (ERKs) 1 and/or 2 or another kinase downstream of MEK1 phosphorylate Ser523 in response to GH. Other ERK activators, phorbol 12-myristate 13-acetate and epidermal growth factor, also stimulate phosphorylation of Ser523. When Ser523 in JAK2 was mutated, JAK2 kinase activity as well as GH-dependent tyrosyl phosphorylation of JAK2 and Stat5 was enhanced, suggesting that phosphorylation of Ser523 inhibits JAK2 kinase activity. We hypothesize that phosphorylation of Ser523 in JAK2 by ERKs 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner to dampen activation of JAK2 in response to GH and provides a mechanism by which prior exposure to environmental factors that regulate Ser523 phosphorylation might modulate the cell's response to GH.
Mazurkiewicz-Munoz
Anna M
AM
Graduate Program in Cellular and Molecular Biology, The University of Michigan Medical School, Ann Arbor, MI 48109-0622, USA.
Argetsinger
Lawrence S
LS
Kouadio
Jean-Louis K
JL
Stensballe
Allan
A
Jensen
Ole N
ON
Cline
Joel M
JM
Carter-Su
Christin
C
D016475:3T3 Cells; D000409:Alanine / Q000235:genetics; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D053614:Janus Kinase 2; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation / Q000235:genetics; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism*; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002070:Butadienes; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C494097:Stat5b protein, rat; C113580:U 0126; D010768:Phosphoserine; D019000:Phosphotyrosine; D004815:Epidermal Growth Factor; D013006:Growth Hormone; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D048369:MAP Kinase Kinase 1; D013755:Tetradecanoylphorbol Acetate; D000409:Alanine