Novel involvement of RhebL1 in sphingosylphosphorylcholine-induced keratin phosphorylation and reorganization: Binding to and activation of AKT1
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Hyun Ji Kim1, Hyun Jung Byun1, Mi Kyung Park1, Eun Ji Kim1, Gyeoung Jin Kang1, Chang Hoon Lee1
1College of Pharmacy, Dongguk University, Seoul 100-715, Republic of Korea
Chang Hoon Lee, email: [email protected]
Keywords: sphingosylphosphorylcholine, RhebL1, AKT1, keratin reorganization, migration
Received: December 12, 2016 Accepted: February 06, 2017 Published: February 15, 2017
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.
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