Jak2 tyrosine kinase mediates angiotensin II-dependent inactivation of ERK2 via induction of mitogen-activated protein kinase phosphatase 1.
Previous work has shown that inhibition of Jak2 via the pharmacological compound AG490 blocks the angiotensin II (Ang II)-dependent activation of ERK2, thereby suggesting an essential role of Jak2 in ERK activation. However, recent studies have thrown into question the specificity of AG490 and therefore the role of Jak2 in ERK activation. To address this, we reconstituted an Ang II signaling system in a Jak2-/-cell line and measured the ability of Ang II to activate ERK2 in these cells. Controls for this study were the same cells expressing Jak2 via the addition of a Jak2 expression plasmid. In the cells expressing Jak2, Ang II induced a marked increase in ERK2 activity as measured by Western blot analysis and in vitro kinase assays. ERK2 activity returned to basal levels within 30 min. However, in the cells lacking Jak2, Ang II treatment resulted in ERK2 activation that did not return to basal levels until 120 min after ligand addition. Analysis of phosphatase gene expression revealed that Ang II induced mitogen-activated protein kinase phosphatase 1 (MKP-1) expression in cells expressing Jak2 but failed to induce MKP-1 expression in cells lacking Jak2. Therefore, our results suggest that Jak2 is not required for Ang II-induced ERK2 activation. Rather Jak2 is required for Ang II-induced ERK2 inactivation via induction of MKP-1 gene expression.
Sandberg
Eric M
EM
Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL 32610, USA.
Ma
Xianyue
X
VonDerLinden
Dannielle
D
Godeny
Michael D
MD
Sayeski
Peter P
PP
D000804:Angiotensin II / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1; D004789:Enzyme Activation; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000502:physiology*; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D051419:Paxillin; D010749:Phosphoprotein Phosphatases; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D054645:Protein Phosphatase 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic
D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; C496061:PXN protein, human; D051419:Paxillin; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D000804:Angiotensin II; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases