title: Novel role of presenilins in maturation and transport of integrin beta 1.
abstract: Presenilins (PSs) play important roles in modulating the trafficking and maturation of several membrane proteins. However, the target membrane proteins whose trafficking and maturation are regulated by PS are largely unknown. By characterizing PS-deficient fibroblasts, we found that integrin beta1 maturation is promoted markedly in PS1 and PS2 double-deficient fibroblasts and moderately in PS1- or PS2-deficient fibroblasts; in contrast, nicastrin maturation is completely inhibited in PS1 and PS2 double-deficient fibroblasts. Subcellular fractionation analysis demonstrated that integrin beta1 maturation is promoted in the Golgi apparatus. The mature integrin beta1 with an increased expression level was delivered to the cell surface, which resulted in an increased cell surface expression level of mature integrin beta1 in PS1 and PS2 double-deficient fibroblasts. PS1 and PS2 double-deficient fibroblasts exhibited an enhanced ability to adhere to culture dishes coated with integrin beta1 ligands, namely, fibronectin and laminin. The inhibition of gamma-secretase activity enhances neither integrin beta1 maturation nor the adhesion of wild-type cells. Moreover, PS deficiency also promoted the maturation of integrins alpha3 and alpha5 and the cell surface expression of integrin alpha3. Integrins alpha3 and alpha5 were coimmunoprecipitated with integrin beta1, suggesting the formation of the functional heterodimers integrins alpha3beta1 and alpha5beta1. Note that integrin beta1 exhibited features opposite those of nicastrin in terms of maturation and trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus in PS1 and PS2 double-deficient fibroblasts. Our results therefore suggest that PS regulates the maturation of membrane proteins in opposite directions and cell adhesion by modulating integrin maturation.
authors.affiliation: Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, NCGG, 36-3 Gengo, Morioka, Obu, Aichi 474-8522, Japan. kunzou@iwate-med.ac.jp
authors.forename: Kun
authors.initials: K
authors.lastname: Zou
authors.forename: Takashi
authors.initials: T
authors.lastname: Hosono
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nakamura
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Shiraishi
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Yanagisawa
authors.forename: Makoto
authors.initials: M
authors.lastname: Michikawa
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis / Q000378:metabolism*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053764:Presenilin-1 / Q000172:deficiency / Q000502:physiology*; D053766:Presenilin-2 / Q000172:deficiency / Q000502:physiology*; D021381:Protein Transport / Q000235:genetics
chemical_list: D019012:Integrin beta1; D008565:Membrane Proteins; D053764:Presenilin-1; D053766:Presenilin-2