title: A dystroglycan/plectin scaffold mediates mechanical pathway bifurcation in lung epithelial cells.
abstract: In alveolar epithelial cells (AECs), the membrane-anchored proteoglycan dystroglycan (DG) is a mechanoreceptor that transmits mechanical stretch forces to activate independently the ERK1/2 and the adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling cascades in a process called pathway bifurcation. We tested the hypothesis that the cytoskeleton cross-linker plectin, known to bind both DG and AMPK in muscle cells, acts as a scaffold to regulate DG-mediated mechanical stimulation and pathway bifurcation. We demonstrate that plectin and DG form a complex in AECs and that this complex interacts with ERK1/2 and AMPK. Plectin knockdown reduces DG interaction with AMPK but not with ERK1/2. Despite this, mechanoactivation of both signaling pathways is significantly attenuated in AECs deficient in plectin. Thus, DG has the dual role of mechanical receptor and scaffold for ERK1/2, whereas plectin acts as a scaffold for AMPK signaling but is also required for DG-mediated ERK1/2 activation. We conclude that the DG-plectin complex plays a central role in transmitting mechanical stress from the extracellular matrix to the cytoplasm.
authors.affiliation: Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Desire
authors.initials: D
authors.lastname: Takawira
authors.forename: G R Scott
authors.initials: GR
authors.lastname: Budinger
authors.forename: Susan B
authors.initials: SB
authors.lastname: Hopkinson
authors.forename: Jonathan C R
authors.initials: JC
authors.lastname: Jones
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D051190:Plectin / Q000235:genetics / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051190:Plectin; D049030:Dystroglycans; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases