title: Fer kinase regulates cell migration through α-dystroglycan glycosylation.
abstract: Glycans of α-dystroglycan (α-DG), which is expressed at the epithelial cell-basement membrane (BM) interface, play an essential role in epithelium development and tissue organization. Laminin-binding glycans on α-DG expressed on cancer cells suppress tumor progression by attenuating tumor cell migration from the BM. However, mechanisms controlling laminin-binding glycan expression are not known. Here, we used small interfering RNA (siRNA) library screening and identified Fer kinase, a non-receptor-type tyrosine kinase, as a key regulator of laminin-binding glycan expression. Fer overexpression decreased laminin-binding glycan expression, whereas siRNA-mediated down-regulation of Fer kinase increased glycan expression on breast and prostate cancer cell lines. Loss of Fer kinase function via siRNA or mutagenesis increased transcription levels of glycosyltransferases, including protein O-mannosyltransferase 1, β3-N-acetylglucosaminyltransferase 1, and like-acetylglucosaminyltransferase that are required to synthesize laminin-binding glycans. Consistently, inhibition of Fer expression decreased cell migration in the presence of laminin fragment. Fer kinase regulated STAT3 phosphorylation and consequent activation, whereas knockdown of STAT3 increased laminin-binding glycan expression on cancer cells. These results indicate that the Fer pathway negatively controls expression of genes required to synthesize laminin-binding glycans, thus impairing BM attachment and increasing tumor cell migration.
authors.affiliation: Glycobiology Unit, Tumor Microenvironment Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yoneyama
authors.forename: Kiyohiko
authors.initials: K
authors.lastname: Angata
authors.forename: Xingfeng
authors.initials: X
authors.lastname: Bao
authors.forename: Sara
authors.initials: S
authors.lastname: Courtneidge
authors.forename: Sumit K
authors.initials: SK
authors.lastname: Chanda
authors.forename: Minoru
authors.initials: M
authors.lastname: Fukuda
mesh_terms: D001485:Basement Membrane / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D049030:Dystroglycans / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006031:Glycosylation; D006801:Humans; D034882:Lamins / Q000378:metabolism; D008364:Mannosyltransferases / Q000235:genetics; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism
chemical_list: D034882:Lamins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C052602:proto-oncogene protein c-fes-fps; D049030:Dystroglycans; D014443:Tyrosine; C117674:LARGE1 protein, human; D008364:Mannosyltransferases; D017351:N-Acetylglucosaminyltransferases; C082696:protein O-mannosyltransferase; C542575:B4GAT1 protein, human; D011505:Protein-Tyrosine Kinases