Phosphorylation at the cyclin-dependent kinases site (Thr85) of parathyroid hormone-related protein negatively regulates its nuclear localization

被引:66
作者
Lam, MHC
House, CM
Tiganis, T
Mitchelhill, KI
Sarcevic, B
Cures, A
Ramsay, R
Kemp, BE
Martin, TJ
Gillespie, MT
机构
[1] Univ Melbourne, St Vincents Inst Med Res, Fitzroy, Vic 3065, Australia
[2] Univ Melbourne, Dept Med, Fitzroy, Vic 3065, Australia
[3] St Vincents Hosp, Canc Res Program, Garvan Inst Med Res, Sydney, NSW 2010, Australia
[4] Peter MacCallum Canc Inst, Melbourne, Vic 3002, Australia
关键词
D O I
10.1074/jbc.274.26.18559
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Parathyroid hormone-related protein (PTHrP) is expressed by a wide variety of cells and is considered to act as a secreted factor; however, evidence is accumulating for it to act in an intracrine manner. We have determined that PTHrP localizes to the nucleus at the G(1) phase of the cell cycle and is transported to the cytoplasm when cells divide. PTHrP contains a putative nuclear localization sequence (NLS) (residues 61-94) similar to that of SV40 T-antigen, which may be implicated in the nuclear import of the molecule. We identified that Thr(85) immediately prior to the NLS of PTHrP was phosphorylated by CDC2-CDK2 and phosphorylation was cell cycle-dependent. Mutation of Thr(85) to Ala(85) resulted in nuclear accumulation of PTHrP, while mutation to GIu(85) to mimic a phosphorylated residue resulted in localization of PTHrP to the cytoplasm. Combined, the data demonstrate that the intracellular localization of PTHrP is phosphorylation- and cell cycle-dependent, and such control further supports a potential intracellular role (10, 34, 35) for PTHrP.
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收藏
页码:18559 / 18566
页数:8
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