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Cellular and Molecular Life Sciences

, Volume 75, Issue 9, pp 1671–1685 | Cite as

Low density lipoprotein receptor-related protein 1 couples β1 integrin activation to degradation

  • Lukasz Wujak
  • Ralph T. Böttcher
  • Oleg Pak
  • Helena Frey
  • Elie El Agha
  • Ying Chen
  • Sigrid Schmitt
  • Saverio Bellusci
  • Liliana Schaefer
  • Norbert ‎Weissmann
  • Reinhard Fässler
  • Malgorzata Wygrecka
Original Article

Abstract

Low density lipoprotein receptor-related protein (LRP) 1 modulates cell adhesion and motility under normal and pathological conditions. Previous studies documented that LRP1 binds several integrin receptors and mediates their trafficking to the cell surface and endocytosis. However, the mechanism by which LRP1 may regulate integrin activation remains unknown. Here we report that LRP1 promotes the activation and subsequent degradation of β1 integrin and thus supports cell adhesion, spreading, migration and integrin signaling on fibronectin. LRP1 interacts with surface β1 integrin, binds the integrin activator kindlin2 and stimulates β1 integrin–kindlin2 complex formation. Specifically, serine 76 in the LRP1 cytoplasmic tail is crucial for the interaction with kindlin2, β1 integrin activation and cell adhesion. Interestingly, a loss of LRP1 induces the accumulation of several integrin receptors on the cell surface. Following internalization, intracellular trafficking of integrins is driven by LRP1 in a protein kinase C- and class II myosin-dependent manner. Ultimately, LRP1 dictates the fate of endocytosed β1 integrin by directing it down the pathway of lysosomal and proteasomal degradation. We propose that LRP1 mediates cell adhesion by orchestrating a multi-protein pathway to activate, traffic and degrade integrins. Thus, LRP1 may serve as a focal point in the integrin quality control system to ensure a firm connection to the extracellular matrix.

Keywords

Integrins Adhesion Lysosomes LRP1 

Abbreviations

α2M

α2-Macroglobulin

Baf

Bafilomycin A1

Bleb

Blebbistatin

ECM

Extracellular matrix

ESCRT

Endosomal sorting complex required for transport

FAK

Focal adhesion kinase

LRP1

Low density lipoprotein receptor-related protein 1

MEF

Mouse embryonic fibroblasts

MYH9

Myosin heavy chain 9

pHLF

Primary human lung fibroblasts

PKC

Protein kinase C

PMA

Phorbol 12-myristate 13-acetate

SNX17

Sorting nexin 17

TGF-β

Transforming growth factor

Notes

Acknowledgements

We thank Yvonne Horn, Markus Schwinn and Horst Thiele for their excellent technical assistance. This work was supported the German Research Foundation (WY119/1-3 to MW; SFB 815, Project A5 and SCHA1082/6 to LS), Excellence Cluster Cardio-Pulmonary System (ECCPS to LW and MW) and the German Center for Lung Research (to MW).

Supplementary material

18_2017_2707_MOESM1_ESM.pdf (639 kb)
Supplementary material 1 (PDF 639 kb)
18_2017_2707_MOESM2_ESM.mov (6.6 mb)
Supplementary material 2 (MOV 6743 kb)

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  • Lukasz Wujak
    • 1
  • Ralph T. Böttcher
    • 3
    • 4
  • Oleg Pak
    • 2
  • Helena Frey
    • 5
  • Elie El Agha
    • 2
  • Ying Chen
    • 1
  • Sigrid Schmitt
    • 1
  • Saverio Bellusci
    • 2
  • Liliana Schaefer
    • 5
  • Norbert ‎Weissmann
    • 2
  • Reinhard Fässler
    • 3
  • Malgorzata Wygrecka
    • 1
  1. 1.Department of BiochemistryJustus Liebig UniversityGiessenGermany
  2. 2.Excellence Cluster Cardio-Pulmonary SystemJustus Liebig UniversityGiessenGermany
  3. 3.Max Planck Institute of BiochemistryMartinsriedGermany
  4. 4.German Center for Cardiovascular Research (DZHK)Munich Heart AllianceMunichGermany
  5. 5.Institute of Pharmacology and ToxicologyGoethe University School of Medicine, University HospitalFrankfurt am MainGermany

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