title: p90 RSK2 mediates antianoikis signals by both transcription-dependent and -independent mechanisms.
abstract: How invasive and metastatic tumor cells evade anoikis induction remains unclear. We found that knockdown of RSK2 sensitizes diverse cancer cells to anoikis induction, which is mediated through phosphorylation targets including apoptosis signal-regulating kinase 1 (ASK1) and cyclic AMP (cAMP) response element-binding protein (CREB). We provide evidence to show that RSK2 inhibits ASK1 by phosphorylating S83, T1109, and T1326 through a novel mechanism in which phospho-T1109/T1326 inhibits ATP binding to ASK1, while phospho-S83 attenuates ASK1 substrate MKK6 binding. Moreover, the RSK2→CREB signaling pathway provides antianoikis protection by regulating gene expression of protein effectors that are involved in cell death regulation, including the antiapoptotic factor protein tyrosine kinase 6 (PTK6) and the proapoptotic factor inhibitor-of-growth protein 3 (ING3). PTK6 overexpression or ING3 knockdown in addition to ASK1 knockdown further rescued the increased sensitivity to anoikis induction in RSK2 knockdown cells. These data together suggest that RSK2 functions as a signal integrator to provide antianoikis protection to cancer cells in both transcription-independent and -dependent manners, in part by signaling through ASK1 and CREB, and contributes to cancer cell invasion and tumor metastasis.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Lingtao
authors.initials: L
authors.lastname: Jin
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
authors.forename: Shannon
authors.initials: S
authors.lastname: Elf
authors.forename: Gina N
authors.initials: GN
authors.lastname: Alesi
authors.forename: Jun
authors.initials: J
authors.lastname: Fan
authors.forename: Hee-Bum
authors.initials: HB
authors.lastname: Kang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Wang
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.forename: Jack
authors.initials: J
authors.lastname: Taunton
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: Meghan
authors.initials: M
authors.lastname: Tucker
authors.forename: Ting-Lei
authors.initials: TL
authors.lastname: Gu
authors.forename: Zhuo G
authors.initials: ZG
authors.lastname: Chen
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.forename: Sumin
authors.initials: S
authors.lastname: Kang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D023102:Anoikis / Q000502:physiology*; D045744:Cell Line, Tumor / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D018398:Homeodomain Proteins; C459806:ING3 protein, human; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human