Phosphorylation of protein-tyrosine phosphatase PTP-1B on identical sites suggests activation of a common signaling pathway during mitosis and stress response in mammalian cells.
PTP-1B is a widely expressed non-transmembrane tyrosine-specific phosphatase. Previous studies indicated that, at mitosis, PTP-1B undergoes phosphorylation on two sites, 352Ser-Pro-Leu-Asn and 386Ser-Pro-Ala-Lys. Although the Ser-386 site can be phosphorylated by Cyclin B/Cdc2 in vitro, the kinase for the Ser-352 site is unknown. We have found that these phosphorylation events are not unique to normal mitosis. Instead, treatment with many, but not all, stress stimuli, in particular osmotic shock and certain phosphatase and protein synthesis inhibitors, leads to phosphorylation of PTP-1B. Tryptic phosphopeptide and mutant analysis reveals that, as in mitosis, stress-induced PTP-1B phosphorylation involves both Ser-352 and Ser-386. Activation of the proline-directed kinases Erk1/2, JNKs, and p38 was neither necessary nor sufficient for stress-induced PTP-1B phosphorylation. Our data suggest the existence of a novel mitogen-activated protein kinase pathway in mammalian cells, which is activated at mitosis and in response to osmotic shock and other stresses and results in PTP-1B phosphorylation. This pathway may be similar to the recently described Spc1/Sty1 pathway in Schizosaccharomyces pombe.
Shifrin
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Cancer Biology Program and Division of Hematology-Oncology, Department of Medicine, Beth Israel Hospital, Boston, Massachusetts 02215, USA.
Davis
R J
RJ
Neel
B G
BG
D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007700:Kinetics; D008322:Mammals; D020928:Mitogen-Activated Protein Kinases; D008938:Mitosis; D016297:Mutagenesis, Site-Directed; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation; D017354:Point Mutation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction; D013312:Stress, Physiological; D013379:Substrate Specificity; D014162:Transfection
D011994:Recombinant Proteins; D012694:Serine; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D017027:Protein Tyrosine Phosphatases; D015739:Nocodazole