NUP98 fusion oncoproteins interact with the APC/C(Cdc20) as a pseudosubstrate and prevent mitotic checkpoint complex binding.
NUP98 is a recurrent partner gene in translocations causing acute myeloid leukemias and myelodisplastic syndrome. The expression of NUP98 fusion oncoproteins has been shown to induce mitotic spindle defects and chromosome missegregation, which correlate with the capability of NUP98 fusions to cause mitotic checkpoint attenuation. We show that NUP98 oncoproteins physically interact with the APC/C(Cdc20) in the absence of the NUP98 partner protein RAE1, and prevent the binding of the mitotic checkpoint complex to the APC/C(Cdc20). NUP98 oncoproteins require the GLEBS-like domain present in their NUP98 moiety to bind the APC/C(Cdc20). We found that NUP98 wild-type is a substrate of APC/C(Cdc20) prior to mitotic entry, and that its binding to APC/C(Cdc20) is controlled via phosphorylation of a PEST sequence located within its C-terminal portion. We identify S606, within the PEST sequence, as a key target site, whose phosphorylation modulates the capability of NUP98 to interact with APC/C(Cdc20). We finally provide evidence for an involvement of the peptidyl-prolyl isomerase PIN1 in modulating the possible conformational changes within NUP98 that lead to its dissociation from the APC/C(Cdc20) during mitosis. Our results provide novel insight into the mechanisms underlying the aberrant capability of NUP98 oncoproteins to interact with APC/C(Cdc20) and to interfere with its function.
a Department of Life Sciences , University of Modena and Reggio Emilia , Modena , Italy.
Valentina
V
Salsi
a Department of Life Sciences , University of Modena and Reggio Emilia , Modena , Italy.
Sebastian
S
Fantini
a Department of Life Sciences , University of Modena and Reggio Emilia , Modena , Italy.
Vincenzo
V
Zappavigna
D064199:Cdc20 Proteins / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints; D064246:Mad2 Proteins; D008938:Mitosis; D000072340:NIMA-Interacting Peptidylprolyl Isomerase / Q000378:metabolism; D028861:Nuclear Pore Complex Proteins / Q000737:chemistry / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011485:Protein Binding; D000072417:Protein Domains; D055550:Protein Stability; D013379:Substrate Specificity
D064199:Cdc20 Proteins; D064246:Mad2 Proteins; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D028861:Nuclear Pore Complex Proteins; C465451:Nup98 protein, human; D015514:Oncogene Proteins, Fusion; C577488:CDC20 protein, human
NUP98; acute myeloid leukemia; anaphase promoting complex; cell cycle; mitotic checkpoint; myelodisplastic syndrome; nucleoporins; oncogenes