Tyrosine phosphatase SHP-2 is a regulator of p27(Kip1) tyrosine phosphorylation.
Tyrosine phosphorylation of the cell cycle regulator p27(Kip1) plays a crucial role in its binding to cyclin dependent kinases and its subcellular localization. While Src and Bcr-Abl were shown to be responsible for tyrosine phosphorylation, no data are available on the dephosphorylation of p27(Kip1) and the phosphatase involved. Considering the associated dephosphorylation as a pivotal event in the regulation of cell cycle proteins, we focused on the tyrosine phosphatase SHP-2, which is regulated in promyelocytic leukemia cells on G-CSF stimulation. SHP-2 was thus found in association with p27(Kip1) and the G-CSF receptor, and we observed a nuclear translocation of SHP-2 on G-CSF stimulation. Using a catalytically inactive form of SHP-2 and siRNA directed against SHP-2, we could demonstrate the involvement of SHP-2 in tyrosine dephosphorylation of p27(Kip1). Moreover, SHP-2 was strongly activated on G-CSF stimulation and specifically dephosphorylated p27(Kip1) in vitro. Most importantly, we could illustrate that SHP-2 modulates p27(Kip1) stability and contributes to p27(Kip1)-mediated cell cycle progression. Taken together, our results demonstrate that SHP-2 is a key regulator of p27(Kip1) tyrosine phosphorylation.
Tossidou
Irini
I
Nephrologie, Medizinische Hochschule Hannover (MHH), Hannover, Germany.
Dangers
Marc
M
Koch
Alexandra
A
Brandt
Dominique T
DT
Schiffer
Mario
M
Kardinal
Christian
C
D002460:Cell Line; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism*; D034741:RNA, Small Interfering; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases / Q000378:metabolism
D034741:RNA, Small Interfering; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases