title: Novel involvement of RhebL1 in sphingosylphosphorylcholine-induced keratin phosphorylation and reorganization: Binding to and activation of AKT1.
abstract: Sphingosylphosphorylcholine induces keratin phosphorylation and reorganization, and increases viscoelasticity of metastatic cancer cells such as PANC-1 cells. However, the mechanism involved in sphingosylphosphorylcholine-induced keratin phosphorylation and reorganization is largely unknown. Sphingosylphosphorylcholine dose- and time-dependently induces the expression of RhebL1. The involvement of RhebL1 in sphingosylphosphorylcholine-induced events including keratin 8 (K8) phosphorylation, reorganization, migration and invasion was examined. Gene silencing of RhebL1 suppressed the sphingosylphosphorylcholine-induced events and overexpression of RhebL1 enhanced those events even without sphingosylphosphorylcholine treatment. We examined whether the G protein function of RhebL1 induces K8 phosphorylation using constitutively active RhebL1Q64L and dominant negative RhebL1D60K. G protein activity of RhebL1 is involved in sphingosylphosphorylcholine-induced K8 phosphorylation. We found that RhebL1 binds and activates AKT1. G protein activity of RhebL1 is involved in the binding and activation of AKT1. MK2206 (AKT inhibitor) and gene silencing of AKT1 inhibited the sphingosylphosphorylcholine-induced events, whereas overexpression of activated-AKT1 induced K8 phosphorylation, reorganization, migration and invasion even without sphingosylphosphorylcholine treatment.The collective results indicate that RhebL1 is involved in sphingosylphosphorylcholine-induced events in A549 lung cancer cells via binding to AKT1 leading to activation of it. These results suggest that suppression of RhebL1 or inhibition of RhebL1's binding to AKT1 might be a novel way that prevents changes in the physical properties of metastatic cancer cells.
authors.affiliation: College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Hyun Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Byun
authors.affiliation: College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Mi Kyung
authors.initials: MK
authors.lastname: Park
authors.affiliation: College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Gyeoung Jin
authors.initials: GJ
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019204:GTP-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007633:Keratins / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009367:Neoplasm Staging; D010766:Phosphorylation / Q000187:drug effects; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C504241:RHEBL1 protein, human; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D007633:Keratins; D051057:Proto-Oncogene Proteins c-akt; D019204:GTP-Binding Proteins; D018631:ras Proteins; D013110:Sphingosine
keywords: AKT1; RhebL1; keratin reorganization; migration; sphingosylphosphorylcholine