title: Merlin-deficient human tumors show loss of contact inhibition and activation of Wnt/β-catenin signaling linked to the PDGFR/Src and Rac/PAK pathways.
abstract: Neurofibromatosis type 2 (NF2) is an inherited predisposition cancer syndrome characterized by the development of multiple benign tumors in the nervous system including schwannomas, meningiomas, and ependymomas. Using a disease model comprising primary human schwannoma cells, we previously demonstrated that adherens junctions (AJs) are impaired in schwannoma cells because of a ubiquitous, upregulated Rac activity. However, the mechanism by which loss of contact inhibition leads to proliferation remains obscure in merlin-deficient tumors. In this study, we show that proliferative Wnt/β-catenin signaling is elevated as active β-catenin (dephosphorylated at serine 37 and threoine 41) localizes to the nucleus and the Wnt targets genes c-myc and cyclin D1 are upregulated in confluent human schwannoma cells. We demonstrate that Rac effector p21-activated kinase 2 (PAK2) is essential for the activation of Wnt/β-catenin signaling because depletion of PAK2 suppressed active β-catenin, c-myc, and cyclin D1. Most importantly, the link between the loss of the AJ complex and the increased proliferation in human schwannoma cells is connected by Src and platelet-derived growth factor receptor-induced tyrosine 654 phosphorylation on β-catenin and associated with degradation of N-cadherin. We also demonstrate that active merlin maintains β-catenin and N-cadherin complex at the plasma membrane through direct regulation. Finally, we demonstrate that phosphorylation of tyrosine 654 is critical for the increased proliferation in human schwannoma cells because overexpression of a Y654F mutant β-catenin reduces hyperproliferation of schwannoma cells. We suggest a model that these pathways are coordinated and relevant for proliferation in merlin-deficient tumors.
authors.affiliation: Clinical Neurobiology, Peninsula College of Medicine and Dentistry, University of Plymouth, Plymouth, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ercolano
authors.forename: Sylwia
authors.initials: S
authors.lastname: Ammoun
authors.forename: M Caroline
authors.initials: MC
authors.lastname: Schmid
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Barczyk
authors.forename: Clemens Oliver
authors.initials: CO
authors.lastname: Hanemann
mesh_terms: D015820:Cadherins / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation; D003260:Contact Inhibition / Q000235:genetics*; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D009442:Neurilemmoma / Q000235:genetics* / Q000378:metabolism*; D025581:Neurofibromin 2 / Q000172:deficiency* / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D018909:src Homology Domains; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D015820:Cadherins; D025581:Neurofibromin 2; D034741:RNA, Small Interfering; D051153:Wnt Proteins; D051176:beta Catenin; D017479:Receptors, Platelet-Derived Growth Factor; D019061:src-Family Kinases; D054462:p21-Activated Kinases; D020830:rac1 GTP-Binding Protein