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. 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.
Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503.
Lia
L
Tesfay
Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503.
Veronique V
VV
Schulz
Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503.
Sander B
SB
Frank
Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503.
Laura E
LE
Lamb
Laboratory of Integrin Signaling and Tumorigenesis, Van Andel Research Institute, Grand Rapids, MI 49503 cindy.miranti@vai.org.
Cindy K
CK
Miranti
D017209:Apoptosis; D002448:Cell Adhesion / Q000502:physiology; D016923:Cell Death; D002470:Cell Survival / Q000502:physiology; D004847:Epithelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D039201:Integrin alpha3beta1 / Q000235:genetics / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D045170:Matrix Attachment Regions; D010766:Phosphorylation; D061251:Primary Cell Culture; D011467:Prostate; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
D039201:Integrin alpha3beta1; D016023:Integrins; D007797:Laminin; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases