title: The cross-talk of LDL-cholesterol with cell motility: insights from the Niemann Pick Type C1 mutation and altered integrin trafficking.
abstract: Cholesterol is considered indispensible for the recruitment and functioning of integrins in focal adhesions for cell migration. However, the physiological cholesterol pools that control integrin trafficking and focal adhesion assembly remain unclear. Using Niemann Pick Type C1 (NPC) mutant cells, which accumulate Low Density lipoprotein (LDL)-derived cholesterol in late endosomes (LE), several recent studies indicate that LDL-cholesterol has multiple roles in regulating focal adhesion dynamics. Firstly, targeting of endocytosed LDL-cholesterol from LE to focal adhesions controls their formation at the leading edge of migrating cells. Other newly emerging literature suggests that this may be coupled to vesicular transport of integrins, Src kinase and metalloproteases from the LE compartment to focal adhesions. Secondly, our recent work identified LDL-cholesterol as a key factor that determines the distribution and ability of several Soluble NSF Attachment Protein (SNAP) Receptor (SNARE) proteins, key players in vesicle transport, to control integrin trafficking to the cell surface and extracellular matrix (ECM) secretion. Collectively, dietary, genetic and pathological changes in cholesterol metabolism may link with efficiency and speed of integrin and ECM cell surface delivery in metastatic cancer cells. This commentary will summarize how direct and indirect pathways enable LDL-cholesterol to modulate cell motility.
authors.affiliation: a Faculty of Pharmacy; University of Sydney ; Sydney , Australia.
authors.forename: Monira
authors.initials: M
authors.lastname: Hoque
authors.affiliation: b Departament de Biologia Cellular ; Immunologia i Neurociències; Centre de Recerca Biomèdica CELLEX; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Facultat de Medicina; Universitat de Barcelona ; Barcelona , Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Rentero
authors.affiliation: c Cancer Research Program; The Kinghorn Cancer Center; Garvan Institute of Medical Research ; Darlinghurst , Australia.
authors.forename: James R
authors.initials: JR
authors.lastname: Conway
authors.affiliation: d Tissue Repair and Regeneration Program; Institute of Health and Biomedical Innovation; Queensland University of Technology ; Brisbane , Australia.
authors.forename: Rachael Z
authors.initials: RZ
authors.lastname: Murray
authors.affiliation: c Cancer Research Program; The Kinghorn Cancer Center; Garvan Institute of Medical Research ; Darlinghurst , Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.affiliation: b Departament de Biologia Cellular ; Immunologia i Neurociències; Centre de Recerca Biomèdica CELLEX; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS); Facultat de Medicina; Universitat de Barcelona ; Barcelona , Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Enrich
authors.affiliation: a Faculty of Pharmacy; University of Sydney ; Sydney , Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
mesh_terms: D000818:Animals; D002465:Cell Movement; D008078:Cholesterol, LDL / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D022001:Focal Adhesions / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology; D052556:Niemann-Pick Disease, Type C / Q000235:genetics / Q000473:pathology; D020239:Receptor Cross-Talk; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins / Q000378:metabolism
chemical_list: D008078:Cholesterol, LDL; D016023:Integrins; D052067:Soluble N-Ethylmaleimide-Sensitive Factor Attachment Proteins
keywords: SNARE proteins; cell migration; cholesterol; integrin trafficking; late endosomes; low density lipoprotein; niemann pick type C; trans-Golgi-network