title: Protein kinase C-associated kinase regulates NF-κB activation through inducing IKK activation.
abstract: Activation of the transcription factor NF-κB induced by extracellular stimuli requires IKKα and IKKβ kinase activity. How IKKα and IKKβ are activated by various upstream signaling molecules is not fully understood. We previously showed that protein kinase C-associated kinase (PKK, also known as DIK/RIP4), which belongs to the receptor-interacting protein (RIP) kinase family, mediates the B cell activating factor of the TNF family (BAFF)-induced NF-κB activation in diffuse large B cell lymphoma (DLBCL) cell lines. Here we have investigated the mechanism underlying NF-κB activation regulated by PKK. Our results suggest that PKK can activate both the classical and the alternative NF-κB activation pathways. PKK associates with IKKα and IKKβ in mammalian cells and induces activation of both IKKα and IKKβ via phosphorylation of their serine residues 176/180 and 177/181, respectively. Unlike other members of the RIP family that activate NF-κB through a kinase-independent pathway, PKK appears to activate IKK and NF-κB mainly in a kinase-dependent manner. Suppression of PKK expression by RNA interference inhibits phosphorylation of IKKα and IKKβ as well as activation of NF-κB in human cancer cell lines. Thus, PKK regulates NF-κB activation by modulating activation of IKKα and IKKβ in mammalian cells. We propose that PKK may provide a critical link between IKK activation and various upstream signaling cascades, and may represent a potential target for inhibiting abnormal NF-κB activation in human cancers.
authors.affiliation: Department of Biological Sciences, Pusan National University, Busan 609-735, Republic of Korea.
authors.forename: Sang-Woo
authors.initials: SW
authors.lastname: Kim
authors.affiliation: eBioscience, San Diego, CA 92121, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Schifano
authors.affiliation: Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: David
authors.initials: D
authors.lastname: Oleksyn
authors.affiliation: Division of Hematology, University of Colorado, Aurora, CO 80045, USA.
authors.forename: Craig T
authors.initials: CT
authors.lastname: Jordan
authors.affiliation: Department of Pathology, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ryan
authors.affiliation: Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Insel
authors.affiliation: Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
authors.forename: Luojing
authors.initials: L
authors.lastname: Chen
mesh_terms: D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D015759:Ionomycin / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D051550:I-kappa B Kinase; D015759:Ionomycin; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D000097782:NF-kappaB-Inducing Kinase; C417187:RIPK4 protein, human