title: Integrative Analysis of Subcellular Quantitative Proteomics Studies Reveals Functional Cytoskeleton Membrane-Lipid Raft Interactions in Cancer.
abstract: Lipid rafts are dynamic membrane microdomains that orchestrate molecular interactions and are implicated in cancer development. To understand the functions of lipid rafts in cancer, we performed an integrated analysis of quantitative lipid raft proteomics data sets modeling progression in breast cancer, melanoma, and renal cell carcinoma. This analysis revealed that cancer development is associated with increased membrane raft-cytoskeleton interactions, with ∼40% of elevated lipid raft proteins being cytoskeletal components. Previous studies suggest a potential functional role for the raft-cytoskeleton in the action of the putative tumor suppressors PTRF/Cavin-1 and Merlin. To extend the observation, we examined lipid raft proteome modulation by an unrelated tumor suppressor opioid binding protein cell-adhesion molecule (OPCML) in ovarian cancer SKOV3 cells. In agreement with the other model systems, quantitative proteomics revealed that 39% of OPCML-depleted lipid raft proteins are cytoskeletal components, with microfilaments and intermediate filaments specifically down-regulated. Furthermore, protein-protein interaction network and simulation analysis showed significantly higher interactions among cancer raft proteins compared with general human raft proteins. Collectively, these results suggest increased cytoskeleton-mediated stabilization of lipid raft domains with greater molecular interactions as a common, functional, and reversible feature of cancer cells.
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland , Translational Research Institute, Brisbane, Queensland 4102, Australia.
authors.forename: Anup D
authors.initials: AD
authors.lastname: Shah
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland , Translational Research Institute, Brisbane, Queensland 4102, Australia.
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Inder
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland , Translational Research Institute, Brisbane, Queensland 4102, Australia.
authors.forename: Alok K
authors.initials: AK
authors.lastname: Shah
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland , Translational Research Institute, Brisbane, Queensland 4102, Australia.
authors.forename: Alexandre S
authors.initials: AS
authors.lastname: Cristino
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London Hammersmith Campus , London W12 0NN, United Kingdom.
authors.forename: Arthur B
authors.initials: AB
authors.lastname: McKie
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London Hammersmith Campus , London W12 0NN, United Kingdom.
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
authors.affiliation: Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville Victoria 3052, Australia.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Davis
authors.affiliation: The University of Queensland Diamantina Institute, The University of Queensland , Translational Research Institute, Brisbane, Queensland 4102, Australia.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Hill
mesh_terms: D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D002462:Cell Membrane; D003198:Computer Simulation; D003599:Cytoskeleton / Q000737:chemistry / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology / Q000648:ultrastructure*; D010051:Ovarian Neoplasms / Q000473:pathology / Q000648:ultrastructure; D054730:Protein Interaction Domains and Motifs; D020543:Proteome / Q000032:analysis*; D040901:Proteomics / Q000379:methods*
chemical_list: D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; C059785:OPCML protein, human; D020543:Proteome
keywords: cancer progression; computational biology; cytoskeleton; lipid raft; quantitative proteomics