title: Transglutaminase Interaction with α6/β4-Integrin Stimulates YAP1-Dependent ΔNp63α Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation.
abstract: Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem cell survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show that TG2 is constitutively expressed in ECS cells, where it interacts with α6/β4 integrin to stimulate FAK and Src signaling, leading to PI3K activation of phosphoinositide-dependent kinase 1 (PDK1). PDK1 inhibits Hippo signaling, leading to enhanced nuclear accumulation of YAP1, which interacted with and stabilized ΔNp63α to enhance epidermal squamous cell carcinoma spheroid formation, invasion, and migration. Overall, these findings suggest that constitutive TG2 expression results in stabilization of ΔNp63α, leading to maintenance of cancer stem cell properties and enhanced tumor formation. Cancer Res; 76(24); 7265-76. ©2016 AACR.
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Matthew L
authors: ML
authors: Fisher
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Candace
authors: C
authors: Kerr
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Gautam
authors: G
authors: Adhikary
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Dan
authors: D
authors: Grun
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Wen
authors: W
authors: Xu
authors: Department of Chemistry, University of Ottawa, Ottawa, Ontario, Canada.
authors: Jeffrey W
authors: JW
authors: Keillor
authors: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland. reckert@umaryland.edu.|Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland.|Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland.|Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland.
authors: Richard L
authors: RL
authors: Eckert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010750:Phosphoproteins / Q000378:metabolism; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction / Q000502:physiology; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism*; D011503:Transglutaminases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D039161:Integrin alpha6beta4; D010750:Phosphoproteins; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins