title: Hyperactive RAS/PI3-K/MAPK Signaling Cascade in Migration and Adhesion of Nf1 Haploinsufficient Mesenchymal Stem/Progenitor Cells.
abstract: Neurofibromatosis type 1 (NF1) is an autosomal dominant disease caused by mutations in the NF1 tumor suppressor gene, which affect approximately 1 out of 3000 individuals. Patients with NF1 suffer from a range of malignant and nonmalignant manifestations such as plexiform neurofibromas and skeletal abnormalities. We previously demonstrated that Nf1 haploinsufficiency in mesenchymal stem/progenitor cells (MSPCs) results in impaired osteoblastic differentiation, which may be associated with the skeletal manifestations in NF1 patients. Here we sought to further ascertain the role of Nf1 in modulating the migration and adhesion of MSPCs of the Nf1 haploinsufficient (Nf1(+/-)) mice. Nf1(+/-) MSPCs demonstrated increased nuclear-cytoplasmic ratio, increased migration, and increased actin polymerization as compared to wild-type (WT) MSPCs. Additionally, Nf1(+/-) MSPCs were noted to have significantly enhanced cell adhesion to fibronectin with selective affinity for CH271 with an overexpression of its complimentary receptor, CD49e. Nf1(+/-) MSPCs also showed hyperactivation of phosphoinositide 3-kinase (PI3-K) and mitogen activated protein kinase (MAPK) signaling pathways when compared to WT MSPCs, which were both significantly reduced in the presence of their pharmacologic inhibitors, LY294002 and PD0325901, respectively. Collectively, our study suggests that both PI3-K and MAPK signaling pathways play a significant role in enhanced migration and adhesion of Nf1 haploinsufficient MSPCs.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China. yuanzhou@ihcams.ac.cn.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. yuanzhou@ihcams.ac.cn.|Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. yuanzhou@ihcams.ac.cn.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. yonhe@iu.edu.|Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. yonhe@iu.edu.
authors.forename: Yongzheng
authors.initials: Y
authors.lastname: He
authors.affiliation: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. ricsharm@iupui.edu.
authors.forename: Richa
authors.initials: R
authors.lastname: Sharma
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China. xw2318@aliyun.com.|Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. xw2318@aliyun.com.|Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. xw2318@aliyun.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Xing
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. selinaorlando@yahoo.com.|Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. selinaorlando@yahoo.com.
authors.forename: Selina A
authors.initials: SA
authors.lastname: Estwick
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. wu_xiaohua@lilly.com.|Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. wu_xiaohua@lilly.com.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.affiliation: Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. sdrhodes@iupui.edu.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rhodes
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. mx2@iupui.edu.|Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. mx2@iupui.edu.
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. fyang@iu.edu.|Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA. fyang@iu.edu.
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002448:Cell Adhesion; D002465:Cell Movement; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D057895:Haploinsufficiency; D020935:MAP Kinase Signaling System / Q000187:drug effects; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018631:ras Proteins / Q000378:metabolism
chemical_list: D000199:Actins; D001549:Benzamides; D002867:Chromones; D004159:Diphenylamine; D009025:Morpholines; D025542:Neurofibromin 1; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018631:ras Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C506614:mirdametinib
keywords: mesenchymal stem/progenitor cells; neurofibroma; neurofibromatosis 1; oncogene protein p21 (ras)