PP2A interaction with Rb2/p130 mediates translocation of Rb2/p130 into the nucleus in all-trans retinoic acid-treated ovarian carcinoma cells.
One of the mechanisms by which all-trans retinoic acid (ATRA) has been shown to suppress the growth of CAOV3 ovarian carcinoma cells involves an increase in the accumulation of Rb2/p130 protein, a member of the retinoblastoma family of tumor suppressors. This increase in accumulation of RB2/p130 by ATRA results from increased stability of Rb2/p130 protein as a result of an increase in dephosphorylation of the protein by the serine/threonine phosphatase PP2A. We show that upon ATRA treatment, PP2A interacts with the Rb2/p130 C-terminus and specifically dephosphorylates two residues (S1080 and T1097) adjacent to NLS1 and NLS2 of Rb2/p130. Moreover, co-immunoprecipitation studies reveal that Rb2/p130 can form a complex with the nuclear transport proteins, importin α and importin β, binding to the same dephosphorylated NLS1 and NLS2 sites. Finally, mutation of S1080 and T1097 results in retension of Rb2/p130 in the cytoplasm. Our studies suggest that one mechanism by which ATRA treatment of CAOV3 cells induces G0/G1 arrest involves the recruitment of PP2A to the C-terminus of Rb2/p130, resulting in the dephosphorylation of the S1080 and T1097 adjacent to the NLS and the subsequent interaction of Rb2/p130 with importins leading to transport of the Rb2/p130 to the nucleus where it inhibits cell-cycle progression.
Purev
Enkhtsetseg
E
Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Soprano
Dianne R
DR
Soprano
Kenneth J
KJ
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism*; D005260:Female; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008954:Models, Biological; D008969:Molecular Sequence Data; D019913:Nuclear Localization Signals / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D050717:Retinoblastoma-Like Protein p130 / Q000737:chemistry / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology*
D028884:Karyopherins; D019913:Nuclear Localization Signals; D010455:Peptides; D050717:Retinoblastoma-Like Protein p130; D014212:Tretinoin; D054648:Protein Phosphatase 2