Details

Autor(en) / Beteiligte

• Lam, M H
• House, C M
• Tiganis, T
• Mitchelhill, K I
• Sarcevic, B
• Cures, A
• Ramsay, R
• Kemp, B E
• Martin, T J
• Gillespie, M T

Titel

Phosphorylation at the Cyclin-dependent Kinases Site (Thr85) of Parathyroid Hormone-related Protein Negatively Regulates Its Nuclear Localization

Ist Teil von

• The Journal of biological chemistry, 1999-06, Vol.274 (26), p.18559-18566

Ort / Verlag

United States: American Society for Biochemistry and Molecular Biology

Erscheinungsjahr

1999

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 Glu 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.