Regulation of erythropoietin-induced STAT serine phosphorylation by distinct mitogen-activated protein kinases.
The STAT proteins are a family of latent transcription factors that are activated by a wide variety of cytokines. Upon receptor engagement, STATs become tyrosine phosphorylated, translocate to the nucleus, and induce expression of target genes. In addition to tyrosine phosphorylation, maximal activation of some STAT proteins requires serine phosphorylation within the transactivation domain. Here we focus on STAT phosphorylation after engagement of the erythropoietin receptor (EPO-R). In Ba/F3-EPO-R cells, EPO induces tyrosine and serine phosphorylation of STAT1, STAT3, STAT5A, and STAT5B. Identical regions of the EPO-R couple to both tyrosine and serine phosphorylation of each cognate STAT protein. A proximal region of the EPO-R lacking cytoplasmic tyrosines couples to STAT1 and STAT3 phosphorylation as well as ERK and p38(HOG) activation, but not JNK/SAPK. STAT1 serine phosphorylation was perturbed by inhibition of ERK and p38 pathways, whereas only inhibition of ERK activation blocked STAT3 serine phosphorylation in response to EPO. STAT5A/B phosphorylation is downstream of EPO-R Tyr(343), however, STAT5A/B serine phosphorylation is unaffected by either ERK or p38 inhibition. Physiological responses induced by EPO may depend on regulation of serine phosphorylation of the STAT molecules by p38(HOG) and the ERK family of kinases as well as additional serine/threonine kinases.
Haq
Rizwan
R
Institute of Medical Science, Department of Medical Biophysics, University of Toronto, Canada.
Halupa
Adrienne
A
Beattie
Bryan K
BK
Mason
Jacqueline M
JM
Zanke
Brent W
BW
Barber
Dwayne L
DL
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism*; D006801:Humans; D053614:Janus Kinase 2; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008894:Milk Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; D012694:Serine / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D014443:Tyrosine / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D008894:Milk Proteins; D011518:Proto-Oncogene Proteins; D017467:Receptors, Erythropoietin; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; C494095:STAT5B protein, human; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins; D004921:Erythropoietin; D014443:Tyrosine; D012694:Serine; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases