title: TIPE3 is the transfer protein of lipid second messengers that promote cancer.
abstract: More than half of human cancers have aberrantly upregulated phosphoinositide signals; yet how phospholipid signals are controlled during tumorigenesis is not fully understood. We report here that TIPE3 (TNFAIP8L3) is the transfer protein of phosphoinositide second messengers that promote cancer. High-resolution crystal structure of TIPE3 shows a large hydrophobic cavity that is occupied by a phospholipid-like molecule. TIPE3 preferentially captures and shuttles two lipid second messengers, i.e., phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, and increases their levels in the plasma membrane. Notably, human cancers have markedly upregulated TIPE3 expression. Knocking out TIPE3 diminishes tumorigenesis, whereas enforced TIPE3 expression enhances it in vivo. Thus, the function and metabolism of phosphoinositide second messengers are controlled by a specific transfer protein during tumorigenesis.
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Fayngerts
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Camilla L
authors.initials: CL
authors.lastname: Oxley
authors.affiliation: Institute of Immunology, School of Medicine, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Xianglan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Anastassios
authors.initials: A
authors.lastname: Vourekas
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Cathopoulis
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Immunology, School of Medicine, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
authors.affiliation: Institute of Immunology, School of Medicine, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Suxia
authors.initials: S
authors.lastname: Liu
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Honghong
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Lemmon
authors.affiliation: Institute of Immunology, School of Medicine, Shandong University, Jinan, Shandong 250012, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: ygshi@tsinghua.edu.cn.
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: yhc@mail.med.upenn.edu.
authors.forename: Youhai H
authors.initials: YH
authors.lastname: Chen
mesh_terms: D002455:Cell Division; D002470:Cell Survival; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008055:Lipids / Q000502:physiology*; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D015290:Second Messenger Systems; D015398:Signal Transduction
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; C000593651:TNFAIP8L3 protein, human; D011494:Protein Kinases