Casein kinase 2- and protein kinase A-regulated adenomatous polyposis coli and beta-catenin cellular localization is dependent on p38 MAPK.
Skin cancer is the most common form of malignancy in the world with epidemic proportions. Identifying the biochemical and molecular mechanisms underlying the events leading to tumors is paramount to designing new and effective treatments that may aid in treating and/or preventing skin cancers. Herein we identify p38 MAPK, along with its positive modulator, Gadd45a, as important regulators of nucleocytoplasmic shuttling of the adenomatous polyposis coli (APC) tumor suppressor. APC normally functions to block beta-catenin from promoting cell proliferation and migration/invasion. Keratinocytes lacking proper p38 MAPK activation, either due to lack of Gadd45a or through the use of p38 MAPK-specific inhibitors, are unable to effectively transport APC into the nucleus. We also show that p38 MAPK is able to directly associate with and modulate both casein kinase 2 (CK2) and protein kinase A (PKA), which promote and block APC nuclear import, respectively. We demonstrate that p38 MAPK is able to not only enhance CK2 kinase activity but also suppress PKA kinase activity. Moreover, lack of normal p38 MAPK activity in either Gadd45a-null keratinocytes or in p38 MAPK inhibitor treated keratinocytes leads to decreased CK2 activity and increased PKA activity. In either case, disruption of APC nuclear import results in elevated levels of free cellular, and potentially oncogenic, beta-catenin. Numerous tumors, including skin cancers, are associated with high levels of beta-catenin, and our data indicate that p38 MAPK signaling, along with Gadd45a, may provide tumor suppressor-like functions in part by promoting APC nuclear localization and effective beta-catenin regulation.
Hildesheim
Jeffrey
J
Gene Response Section, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892-4255, USA. jh30h@nih.gov
Salvador
Jesus M
JM
Hollander
M Christine
MC
Fornace
Albert J
AJ
D011125:Adenomatous Polyposis Coli / Q000378:metabolism*; D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry*; D000818:Animals; D047390:Casein Kinase II / Q000378:metabolism / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism / Q000502:physiology*; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097642:GADD45 Proteins
D025601:Adenomatous Polyposis Coli Protein; D047390:Casein Kinase II; D018797:Cell Cycle Proteins; D017868:Cyclic AMP-Dependent Protein Kinases; D003598:Cytoskeletal Proteins; D009687:Nuclear Proteins; D015534:Trans-Activators; D051176:beta Catenin; D048051:p38 Mitogen-Activated Protein Kinases; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C499072:Gadd45a protein, mouse