Receptor tyrosine kinase Met promotes cell survival via kinase-independent maintenance of integrin α3β1

Matrix adhesion via integrins is required for cell survival. Adhesion of epithelial cells to laminin via integrin α3β1 was previously shown to activate at least two independent survival pathways. First, integrin α3β1 is required for autophagy-induced cell survival after growth factor deprivation. Se...

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Veröffentlicht in:Molecular biology of the cell 2016-08, Vol.27 (15), p.2493-2504
Hauptverfasser: Tesfay, Lia, Schulz, Veronique V, Frank, Sander B, Lamb, Laura E, Miranti, Cindy K
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container_end_page 2504
container_issue 15
container_start_page 2493
container_title Molecular biology of the cell
container_volume 27
creator Tesfay, Lia
Schulz, Veronique V
Frank, Sander B
Lamb, Laura E
Miranti, Cindy K
description Matrix adhesion via integrins is required for cell survival. Adhesion of epithelial cells to laminin via integrin α3β1 was previously shown to activate at least two independent survival pathways. First, integrin α3β1 is required for autophagy-induced cell survival after growth factor deprivation. Second, integrin α3β1 independently activates two receptor tyrosine kinases, EGFR and Met, in the absence of ligands. EGFR signaling to Erk promotes survival independently of autophagy. To determine how Met promotes cell survival, we inhibited Met kinase activity or blocked its expression with RNA interference. Loss of Met expression, but not inhibition of Met kinase activity, induced apoptosis by reducing integrin α3β1 levels, activating anoikis, and blocking autophagy. Met was specifically required for the assembly of autophagosomes downstream of LC3II processing. Reexpression of wild-type Met, kinase-dead Met, or integrin α3 was sufficient to rescue death upon removal of endogenous Met. Integrin α3β1 coprecipitated and colocalized with Met in cells. The extracellular and transmembrane domain of Met was required to fully rescue cell death and restore integrin α3 expression. Thus Met promotes survival of laminin-adherent cells by maintaining integrin α3β1 via a kinase-independent mechanism.
doi_str_mv 10.1091/mbc.E15-09-0649
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Met was specifically required for the assembly of autophagosomes downstream of LC3II processing. Reexpression of wild-type Met, kinase-dead Met, or integrin α3 was sufficient to rescue death upon removal of endogenous Met. Integrin α3β1 coprecipitated and colocalized with Met in cells. The extracellular and transmembrane domain of Met was required to fully rescue cell death and restore integrin α3 expression. 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subjects Apoptosis
Cell Adhesion - physiology
Cell Death
Cell Survival - physiology
Epithelial Cells - metabolism
Extracellular Matrix - metabolism
Humans
Integrin alpha3beta1 - genetics
Integrin alpha3beta1 - metabolism
Integrins - metabolism
Laminin - metabolism
Male
MAP Kinase Signaling System
Matrix Attachment Regions
Phosphorylation
Primary Cell Culture
Prostate
Proto-Oncogene Proteins c-met - metabolism
Receptor Protein-Tyrosine Kinases - metabolism
Signal Transduction
title Receptor tyrosine kinase Met promotes cell survival via kinase-independent maintenance of integrin α3β1
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