Laminin-6 assembles into multimolecular fibrillar complexes with perlecan and participates in mechanical-signal transduction via a dystroglycan-dependent, integrin-independent mechanism

Jonathan C. R Jones; Kimberly Lane; Susan B Hopkinson; Emilia Lecuona; Robert C Geiger; David A Dean; Eduardo Correa-Meyer; Meredith Gonzales; Kevin Campbell; Jacob I Sznajder; Scott Budinger

doi:10.1242/jcs.02395

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Laminin-6 assembles into multimolecular fibrillar complexes with perlecan and participates in mechanical-signal transduction via a dystroglycan-dependent, integrin-independent mechanism

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Laminin-6 assembles into multimolecular fibrillar complexes with perlecan and participates in mechanical-signal transduction via a dystroglycan-dependent, integrin-independent mechanism

Jonathan C. R Jones, Kimberly Lane, Susan B Hopkinson, Emilia Lecuona, Robert C Geiger, David A Dean, Eduardo Correa-Meyer, Meredith Gonzales, Kevin Campbell, Jacob I Sznajder, …

Journal of cell science, Vol.118(Pt 12), pp.2557-2566

06/15/2005

DOI: 10.1242/jcs.02395

PMCID: PMC2820238

PMID: 15928048

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Abstract

Mechanical ventilation is a valuable treatment regimen for respiratory failure. However, mechanical ventilation (especially with high tidal volumes) is implicated in the initiation and/or exacerbation of lung injury. Hence, it is important to understand how the cells that line the inner surface of the lung [alveolar epithelial cells (AECs)] sense cyclic stretching. Here, we tested the hypothesis that matrix molecules, via their interaction with surface receptors, transduce mechanical signals in AECs. We first determined that rat AECs secrete an extracellular matrix (ECM) rich in anastamosing fibers composed of the α3 laminin subunit, complexed with β1 and γ1 laminin subunits (i.e. laminin-6), and perlecan by a combination of immunofluorescence microscopy and immunoblotting analyses. The fibrous network exhibits isotropic expansion when exposed to cyclic stretching (30 cycles per minute, 10% strain). Moreover, this same stretching regimen activates mitogen-activated-protein kinase (MAPK) in AECs. Stretch-induced MAPK activation is not inhibited in AECs treated with antagonists to α3 or β1 integrin. However, MAPK activation is significantly reduced in cells treated with function-inhibiting antibodies against the α3 laminin subunit and dystroglycan, and when dystroglycan is knocked down in AECs using short hairpin RNA. In summary, our results support a novel mechanism by which laminin-6, via interaction with dystroglycan, transduces a mechanical signal initiated by stretching that subsequently activates the MAPK pathway in rat AECs. These results are the first to indicate a function for laminin-6. They also provide novel insight into the role of the pericellular environment in dictating the response of epithelial cells to mechanical stimulation and have broad implications for the pathophysiology of lung injury.

Matrix receptors

Matrix adhesion

Stretching

Details

Title: Subtitle: Laminin-6 assembles into multimolecular fibrillar complexes with perlecan and participates in mechanical-signal transduction via a dystroglycan-dependent, integrin-independent mechanism
Creators: Jonathan C. R Jones - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
Kimberly Lane - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
Susan B Hopkinson - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
Emilia Lecuona - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
Robert C Geiger - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
David A Dean - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
Eduardo Correa-Meyer - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
Meredith Gonzales - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
Kevin Campbell - Howard Hughes Medical Institute, Roy J. and Lucille A. Carver College of Medicine, Department of Physiology and Biophysics, University of Iowa, 400 Eckstein Medical Research Building, Iowa City, IA 52242, USA
Jacob I Sznajder - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
Scott Budinger - Division of Pulmonary Medicine, Feinberg School of Medicine, Northwestern University, Morton 4-616, 303 East Chicago Avenue, Chicago, IL 60611, USA
Resource Type: Journal article
Publication Details: Journal of cell science, Vol.118(Pt 12), pp.2557-2566
DOI: 10.1242/jcs.02395
PMID: 15928048
PMCID: PMC2820238
NLM abbreviation: J Cell Sci
ISSN: 0021-9533
eISSN: 1477-9137
Language: English
Date published: 06/15/2005
Academic Unit: Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
Record Identifier: 9984020869002771

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