Phosphotyrosine-specific phosphatase PTP-SL regulates the ERK5 signaling pathway.
The duration and the magnitude of mitogen-activated protein kinase (MAPK) activation specifies signal identity and thus allows the regulation of diverse cellular functions by the same kinase cascade. A tight and finely tuned regulation of MAPK activity is therefore critical for the definition of a specific cellular response. We investigated the role of tyrosine-specific phosphatases (PTPs) in the regulation of ERK5. Although unique in its structure, ERK5 is activated in analogy to other MAPKs by dual phosphorylation of threonine and tyrosine residues in its activation motif. In this study we concentrated on whether and how PTP-SL, a kinase-interacting motif-containing PTP, might be involved in the down-regulation of the ERK5 signal. We found that both proteins interact directly with each other in vitro and in intact cells, resulting in mutual modulation of their enzymatic activities. PTP-SL is a substrate of ERK5 and independent of phosphorylation binding to the kinase enhances its catalytic phosphatase activity. On the other hand, interaction with PTP-SL not only down-regulates endogenous ERK5 activity but also effectively impedes the translocation of ERK5 to the nucleus. These findings indicate a direct regulatory influence of PTP-SL on the ERK5 pathway and corresponding downstream responses of the cell.
Buschbeck
Marcus
M
Max Planck Institute for Biochemistry, Department of Molecular Biology, D-82152 Martinsried, Germany.
Eickhoff
Jan
J
Sommer
Marc N
MN
Ullrich
Axel
A
D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000201:enzymology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016716:PC12 Cells; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D011233:Precipitin Tests; D011485:Protein Binding; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7; D015398:Signal Transduction; D013379:Substrate Specificity
D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D019000:Phosphotyrosine; D020928:Mitogen-Activated Protein Kinases; C513469:PTPRR protein, human; D017027:Protein Tyrosine Phosphatases; C513471:Ptprr protein, rat; D054634:Receptor-Like Protein Tyrosine Phosphatases, Class 7