title: Low density lipoprotein receptor-related protein 1 mediated endocytosis of β1-integrin influences cell adhesion and cell migration.
abstract: The low density lipoprotein receptor-related protein 1 (LRP1) has been shown to interact with β1-integrin and regulate its surface expression. LRP1 knock-out cells exhibit altered cytoskeleton organization and decreased cell migration. Here we demonstrate coupled endocytosis of LRP1 and β1-integrin and the involvement of the intracellular NPxY2 motif of LRP1 in this process. Mouse embryonic fibroblasts harboring a knock in replacement of the NPxY2 motif of LRP1 by a multiple alanine cassette (AAxA) showed elevated surface expression of β1-integrin and decreased β1-integrin internalization rates. As a consequence, cell spreading was altered and adhesion rates were increased in our cell model. Cells formed more focal adhesion complexes, whereby in vitro cell migration rates were decreased. Similar results could be observed in a corresponding mouse model, the C57Bl6 LRP1 NPxYxxL knock in mice, therefore, the biochemistry of cellular adhesion was altered in primary cortical neurons. In vivo cell migration experiments demonstrated a disturbance of neuroblast cell migration along the rostral migratory stream. In summary, our results indicate that LRP1 interacts with β1-integrin mediating integrin internalization and thus correlates with downstream signaling of β1-integrin such as focal adhesion dynamics. Consequently, the disturbance of this interaction resulted in a dysfunction in in vivo and in vitro cell adhesion and cell migration.
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Verena K
authors.initials: VK
authors.lastname: Rabiej
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Pflanzner
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Goetze
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Steffen E
authors.initials: SE
authors.lastname: Storck
authors.affiliation: Institute of Physiological Chemistry and Pathobiochemistry, Westfälische Wilhelms-University Muenster, Waldeyerstraße 15, 48149 Muenster, Germany.
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Eble
authors.affiliation: Department of Neuropathology, Heinrich-Heine-University, Moorenstraße 5, 40225 Duesseldorf, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Weggen
authors.affiliation: Institute of Pathophysiology, University Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mueller-Klieser
authors.affiliation: Institute of Pathobiochemistry, University Medical Center of the Johannes Gutenberg-University, Duesbergweg 6, 55099 Mainz, Germany. Electronic address: pietrzik@uni-mainz.de.
authors.forename: Claus U
authors.initials: CU
authors.lastname: Pietrzik
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D004195:Disease Models, Animal; D004705:Endocytosis; D019012:Integrin beta1 / Q000378:metabolism*; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D019012:Integrin beta1; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins
keywords: Adhesion; Cell migration; Focal adhesion; Lipoprotein receptor‐related protein (LPR); β1-integrin