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 (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.

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Diphenylether Derivative as Selective Inhibitor of Protein Tyrosine Phosphatase 1B (PTP1B) Over T-cell Protein Tyrosine Phosphatase (TCPTP) Identified through Virtual Screening

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557511313110006 ◽

2013 ◽

Vol 13 (11) ◽

pp. 1602-1606 ◽

Cited By ~ 6

Author(s):

M. Reddy ◽

Chakshusmathi Ghadiyaram ◽

Sunil Panigrahi ◽

Subramanya Hosahalli ◽

Lakshmi Mangamoori

Keyword(s):

T Cell ◽

Virtual Screening ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Selective Inhibitor ◽

Cell Protein ◽

Protein Tyrosine Phosphatase 1B ◽

Protein Tyrosine

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Loss of T-Cell Protein Tyrosine Phosphatase Induces Recycling of the Platelet-derived Growth Factor (PDGF) β-Receptor but Not the PDGF α-Receptor

Molecular Biology of the Cell ◽

10.1091/mbc.e06-04-0306 ◽

2006 ◽

Vol 17 (11) ◽

pp. 4846-4855 ◽

Cited By ~ 35

Author(s):

Susann Karlsson ◽

Katarzyna Kowanetz ◽

Åsa Sandin ◽

Camilla Persson ◽

Arne Östman ◽

...

Keyword(s):

T Cell ◽

Growth Factor ◽

Cell Surface ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Dominant Negative ◽

Platelet Derived Growth Factor ◽

Cell Protein ◽

Protein Tyrosine ◽

Β Receptor

We have previously shown that the T-cell protein tyrosine phosphatase (TC-PTP) dephosphorylates the platelet-derived growth factor (PDGF) β-receptor. Here, we show that the increased PDGF β-receptor phosphorylation in TC-PTP knockout (ko) mouse embryonic fibroblasts (MEFs) occurs primarily on the cell surface. The increased phosphorylation is accompanied by a TC-PTP–dependent, monensin-sensitive delay in clearance of cell surface PDGF β-receptors and delayed receptor degradation, suggesting PDGF β-receptor recycling. Recycled receptors could also be directly detected on the cell surface of TC-PTP ko MEFs. The effect of TC-PTP depletion was specific for the PDGF β-receptor, because PDGF α-receptor homodimers were cleared from the cell surface at the same rate in TC-PTP ko MEFs as in wild-type MEFs. Interestingly, PDGF αβ-receptor heterodimers were recycling. Analysis by confocal microscopy revealed that, in TC-PTP ko MEFs, activated PDGF β-receptors colocalized with Rab4a, a marker for rapid recycling. In accordance with this, transient expression of a dominant-negative Rab4a construct increased the rate of clearance of cell surface receptors on TC-PTP ko MEFs. Thus, loss of TC-PTP specifically redirects the PDGF β-receptor toward rapid recycling, which is the first evidence of differential trafficking of PDGF receptor family members.

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