Pim-1 negatively regulates the activity of PTP-U2S phosphatase and influences terminal differentiation and apoptosis of monoblastoid leukemia cells.
The levels of Pim-1, a serine/threonine kinase, increase during phorbol myristate acetate (PMA)-induced myeloid cell differentiation. The tyrosine phosphatase PTP-U2S is also associated with PMA-induced differentiation of myeloid cells and has been shown to enhance differentiation and the onset of apoptosis. PTP-U2S contains a Pim-1 phosphorylation consensus sequence, KKRKLTN, which is efficiently phosphorylated by Pim-1. Immunoprecipitated PTP-U2S from U937 cells was phosphorylated by recombinant Pim-1, resulting in a decrease in its phosphatase activity. During PMA-induced differentiation, U937 cells transfected with the dominant negative Pim-1 underwent rapid differentiation and accelerated apoptosis. The opposite effect was observed for wild-type Pim-1. Our results, therefore, provide compelling evidence that Pim-1 functions to negatively regulate PMA-induced differentiation in part through the phosphorylation of PTP-U2S. Together these data suggest that Pim-1 phosphorylates PTP-U2S in vivo to decrease the phosphatase activity that may be necessary to prevent the premature onset of apoptosis following differentiation.
Wang
Z
Z
School of Molecular Biosciences, Washington State University, Pullman, Washington 99164, USA.
Bhattacharya
N
N
Meyer
M K
MK
Seimiya
H
H
Tsuruo
T
T
Tonani
J A
JA
Magnuson
N S
NS
D000595:Amino Acid Sequence; D017209:Apoptosis; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D007700:Kinetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D020298:U937 Cells
D017931:DNA Primers; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; D017027:Protein Tyrosine Phosphatases