The angiotensin II-dependent nuclear translocation of Stat1 is mediated by the Jak2 protein motif 231YRFRR.
In response to angiotensin II, Jak2 autophosphorylates and binds the angiotensin II AT(1) receptor. By studying a variety of Jak2 deletion proteins, we now show that the Jak2 protein motif (231)YRFRR is required for the co-association of this kinase with the AT(1) receptor. We also used a full-length Jak2 protein containing a (231)FAAAA amino acid substitution. Although this protein still autophosphorylated in response to angiotensin II, it did not co-associate with the AT(1) receptor. This uncoupling indicates that AT(1)/Jak2 co-association is not necessary for angiotensin II-induced Jak2 autophosphorylation and that Jak2 autophosphorylation per se is insufficient for AT(1) receptor co-association. In response to angiotensin II, the Jak2-(231)FAAAA mutant will tyrosine phosphorylate Stat1. However, in the absence of AT(1)/Jak2 co-association, Stat1 did not translocate into the cell nucleus and failed to mediate gene transcription. This notable result indicates that Stat1 tyrosine phosphorylation alone is insufficient for Stat1 nuclear translocation. In summary, we now show that, although Jak2-mediated tyrosine phosphorylation of Stat1 is independent of receptor co-association, Jak2-mediated recruitment of Stat1 to the AT(1) receptor is critical for Stat1 nuclear translocation and subsequent gene transcription.
Sayeski
P P
PP
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Ali
M S
MS
Frank
S J
SJ
Bernstein
K E
KE
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017353:Gene Deletion; D053614:Janus Kinase 2; D008156:Luciferases / Q000378:metabolism; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D014616:Vaccinia virus / Q000235:genetics
D000596:Amino Acids; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D000804:Angiotensin II; D014443:Tyrosine; D008156:Luciferases; D011505:Protein-Tyrosine Kinases; D053614:Janus Kinase 2