The T-cell protein tyrosine phosphatase is phosphorylated on Ser-304 by cyclin-dependent protein kinases in mitosis

The T-cell protein tyrosine phosphatase is phosphorylated on Ser-304 by cyclin-dependent protein kinases in mitosis

Two alternatively spliced forms of the human protein tyrosine phosphatase TCPTP (T-cell protein tyrosine phosphatase) exist: a 48 kDa form that is targeted to the endoplasmic reticulum (TC48) and a shorter 45 kDa form that is targeted to the nucleus (TC45). In this study we have identified Ser-304 (...

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Bibliographic Details
Published in:Biochemical journal Vol. 380; no. Pt 3; pp. 939 - 949
Main Authors: Bukczynska, Patricia, Klingler-Hoffmann, Manuela, Mitchelhill, Kenneth I, Lam, Mark H C, Ciccomancini, Melissa, Tonks, Nicholas K, Sarcevic, Boris, Kemp, Bruce E, Tiganis, Tony
Format: Journal Article
Language:English
Published: England 15-06-2004
Subjects:
Animals
Binding Sites - physiology
Cell Cycle - physiology
Cell Line
Cell Line, Tumor
Cercopithecus aethiops
COS Cells - enzymology
Cyclin-Dependent Kinases - metabolism
Gene Expression Regulation, Enzymologic - genetics
HeLa Cells - enzymology
Humans
Isoenzymes
Kidney - cytology
Kidney - embryology
Kidney - enzymology
Mitosis - physiology
Molecular Weight
Phosphorylation
Protein Tyrosine Phosphatase, Non-Receptor Type 2
Protein Tyrosine Phosphatases - chemistry
Protein Tyrosine Phosphatases - genetics
Protein Tyrosine Phosphatases - metabolism
Serine - metabolism
Transfection - methods
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Summary:Two alternatively spliced forms of the human protein tyrosine phosphatase TCPTP (T-cell protein tyrosine phosphatase) exist: a 48 kDa form that is targeted to the endoplasmic reticulum (TC48) and a shorter 45 kDa form that is targeted to the nucleus (TC45). In this study we have identified Ser-304 (Phe301-Asp-His-Ser304-Pro-Asn-Lys307) as a major TCPTP phosphory-lation site and demonstrate that TC45, but not TC48, is phosphorylated on this site in vivo. Phosphorylation of TC45 on Ser-304 was cell cycle-dependent, and increased as cells progressed from G2 into mitosis, but subsided upon mitotic exit. Ser-304 phosphorylation was increased when cells were arrested in mitosis by microtubule poisons such as nocodazole, but remained unaltered when cells were arrested at the G2/M checkpoint by adriamycin. Phosphorylation of Ser-304 did not alter significantly the phosphatase activity or the protein stability of TC45, and had no apparent effect on TC45 localization. Ser-304 phosphorylation was ablated when cells were treated with the CDK (cyclin-dependent protein kinase) inhibitors roscovitine or SU9516, but remained unaltered when ERK1/2 activation was inhibited with the MEK (mitogen-activated protein kinase/extracellular-signal-regulated kinase kinase) inhibitor PD98059. In addition, recombinant CDKs, but not the Polo-like kinase Plk1, phosphorylated Ser-304 in vitro. Our studies identify Ser-304 as a major phosphorylation site in human TCPTP, and the TC45 variant as a novel mitotic CDK substrate.
ISSN:0264-6021
1470-8728
DOI:10.1042/BJ20031780