title: The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors.
abstract: Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4(DCAF1). Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors.
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: J
authors.initials: J
authors.lastname: Lyons-Rimmer
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ammoun
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, UK.|Aston Medical Research Institute, Aston Medical School, Aston University, Birmingham, UK.
authors.forename: J
authors.initials: J
authors.lastname: Müller
authors.affiliation: School of Biomedical and Healthcare Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: E
authors.initials: E
authors.lastname: Lasonder
authors.affiliation: School of Biomedical and Healthcare Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: V
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: E
authors.initials: E
authors.lastname: Ercolano
authors.affiliation: Department of Neuropathology, Derriford Hospital, Plymouth, UK.
authors.forename: D
authors.initials: D
authors.lastname: Hilton
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: I
authors.initials: I
authors.lastname: Taiwo
authors.affiliation: Cell Biology, MRC Laboratory of Molecular Biology, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: Barczyk
authors.affiliation: Institute of Translational and Stratified Medicine, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK.
authors.forename: C O
authors.initials: CO
authors.lastname: Hanemann
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D058990:Molecular Targeted Therapy; D009442:Neurilemmoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D016518:Neurofibromatosis 2 / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D025581:Neurofibromin 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D025581:Neurofibromin 2; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; C097199:KSR-1 protein kinase; C530533:DCAF1 protein, human; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases