RRC ID 38377
著者 Hang Q, Isaji T, Hou S, Im S, Fukuda T, Gu J.
タイトル Integrin α5 Suppresses the Phosphorylation of Epidermal Growth Factor Receptor and Its Cellular Signaling of Cell Proliferation via N-Glycosylation.
ジャーナル J Biol Chem
Abstract Integrin α5β1-mediated cell adhesion regulates a multitude of cellular responses, including cell proliferation, survival, and cross-talk between different cellular signaling pathways. Integrin α5β1 is known to convey permissive signals enabling anchorage-dependent receptor tyrosine kinase signaling. However, the effects of integrin α5β1 on cell proliferation are controversial, and the molecular mechanisms involved in the regulation between integrin α5β1 and receptor tyrosine kinase remain largely unclear. Here we show that integrin α5 functions as a negative regulator of epidermal growth factor receptor (EGFR) signaling through its N-glycosylation. Expression of WT integrin α5 suppresses the EGFR phosphorylation and internalization upon EGF stimulation. However, expression of the N-glycosylation mutant integrin α5, S3-5, which contains fewer N-glycans, reversed the suppression of the EGFR-mediated signaling and cell proliferation. In a mechanistic manner, WT but not S3-5 integrin α5 forms a complex with EGFR and glycolipids in the low density lipid rafts, and the complex formation is disrupted upon EGF stimulation, suggesting that the N-glycosylation of integrin α5 suppresses the EGFR activation through promotion of the integrin α5-glycolipids-EGFR complex formation. Furthermore, consistent restoration of those N-glycans on the Calf-1,2 domain of integrin α5 reinstated the inhibitory effects as well as the complex formation with EGFR. Taken together, these data are the first to demonstrate that EGFR activation can be regulated by the N-glycosylation of integrin α5, which is a novel molecular paradigm for the cross-talk between integrins and growth factor receptors.
巻・号 290(49)
ページ 29345-60
公開日 2015-12-4
DOI 10.1074/jbc.M115.682229
PII S0021-9258(20)39551-X
PMID 26483551
PMC PMC4705939
MeSH Animals Biotinylation CHO Cells Cell Proliferation Cricetinae Cricetulus ErbB Receptors / metabolism* Female Glycosylation* HEK293 Cells HeLa Cells Humans Integrin alpha5 / metabolism* Membrane Microdomains / chemistry Mice Mice, Inbred NOD Mice, SCID Mutation Neoplasm Transplantation Phosphorylation Protein Structure, Tertiary Signal Transduction
IF 4.238
引用数 19
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ヒト・動物細胞 293T(RCB2202) HeLa