Cell cycle-dependent phosphorylation of Disabled-2 by cdc2.
Disabled-2 (Dab2; also known as p96 and DOC-2) is a signal transduction protein that has been implicated in the control of cell growth. Dab2 is known to be a phosphoprotein, but little is known about the kinases that phosphorylate Dab2. We have found that Dab2 phosphorylation is markedly increased during the mitosis phase of the cell cycle. This phosphorylation is blocked by roscovitine, a selective inhibitor of cyclin-dependent kinases. Dab2 robustly coimmunoprecipitates from cells with the cyclin-dependent kinase cdc2, and purified cdc2 can phosphorylate purified Dab2 fusion proteins in vitro on multiple sites. Cellular phosphorylation of Dab2 by cdc2 promotes the association of Dab2 with Pin1, a peptidylprolyl isomerase that regulates the rate of Dab2 dephosphorylation. These findings reveal that Dab2 is differentially phosphorylated during the cell cycle by cdc2 and provide a potential feedback mechanism by which Dab2 inhibition of cell growth and proliferation may be regulated.
He
Junqi
J
Department of Pharmacology, Rollins Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Xu
Jianguo
J
Xu
Xiang-Xi
XX
Hall
Randy A
RA
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009570:Nitriles; D019319:Okadaic Acid / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011722:Pyrethrins / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D065095:Calcineurin Inhibitors; C102885:DAB2 protein, human; D004791:Enzyme Inhibitors; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009570:Nitriles; D011506:Proteins; D011722:Pyrethrins; D025521:Tumor Suppressor Proteins; D019319:Okadaic Acid; C017180:decamethrin; D016203:CDC2 Protein Kinase; D019703:Calcineurin; D010749:Phosphoprotein Phosphatases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase