The laminin binding α3 and α6 integrins cooperate to promote epithelial cell adhesion and growth

• Published in: Matrix biology Vol. 77; pp. 101 - 116
• Main Authors: Yazlovitskaya, Eugenia M., Viquez, Olga M., Tu, Tianxiang, De Arcangelis, Adele, Georges-Labouesse, Elisabeth, Sonnenberg, Arnoud, Pozzi, Ambra, Zent, Roy
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2019; Elsevier Science Ltd; Elsevier
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Basement membrane; Cell adhesion; Cell adhesion & migration; Cell Adhesion - drug effects; Cell Adhesion Molecules - chemistry; Cell Adhesion Molecules - metabolism; Cell Behavior; Cell migration; Cell Movement - drug effects; Cell Proliferation - drug effects; Cellular Biology; Clonal deletion; Collecting duct; Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Extracellular matrix; Extracellular Matrix - chemistry; Extracellular Matrix - drug effects; Extracellular Matrix - metabolism; Fibroblast growth factor 10; Fibroblast Growth Factor 10 - pharmacology; Gene Deletion; Gene Expression Regulation; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - pharmacology; Growth factors; Humans; Integrin alpha3 - genetics; Integrin alpha3 - metabolism; Integrin alpha3beta1 - genetics; Integrin alpha3beta1 - metabolism; Integrin alpha6 - genetics; Integrin alpha6 - metabolism; Integrin alpha6beta1 - genetics; Integrin alpha6beta1 - metabolism; Integrin alpha6beta4 - genetics; Integrin alpha6beta4 - metabolism; Integrins; Intracellular Signaling Peptides and Proteins; Kalinin; Kidney; Kidney Tubules, Collecting - cytology; Kidney Tubules, Collecting - metabolism; Laminin; Laminin - chemistry; Laminin - metabolism; Life Sciences; Mice; Mice, Knockout; Neuronal-glial interactions; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Primary Cell Culture; Protein Binding; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptor; Signal Transduction; TNF Receptor-Associated Factor 6 - genetics; TNF Receptor-Associated Factor 6 - metabolism; TRAF6 protein; Ubiquitin; Receptor; Kidney; Cell migration; Basement membrane
• ISSN: 0945-053X; 1569-1802
• DOI: 10.1016/j.matbio.2018.08.010

Integrins, the major receptors for cell-extracellular matrix (ECM) interactions, regulate multiple cell biological processes including adhesion, migration, proliferation and growth factor-dependent signaling. The principal laminin (LM) binding integrins α3β1, α6β1 and α6β4 are usually co-expressed in cells and bind to multiple laminins with different affinities making it difficult to define their specific function. In this study, we generated kidney epithelial collecting duct (CD) cells that lack both the α3 and α6 integrin subunits. This deletion impaired cell adhesion and migration to LM-332 and LM-511 more than deleting α3 or α6 alone. Cell adhesion mediated by both α3β1 and α6 integrins was PI3K independent, but required K63-linked polyubiquitination of Akt by the ubiquitin-modifying enzyme TRAF6. Moreover, we provide evidence that glial-derived neurotrophic factor (GDNF) and fibroblast growth factor 10 (FGF10)- mediated cell signaling, spreading and proliferation were severely compromised in double integrin α3/α6- but not single α3- or α6-null CD cells. Interestingly, these growth factor-dependent cell functions required both PI3K- and TRAF6-dependent Akt activation. These data suggest that expression of the integrin α3 or α6 subunit is sufficient to mediate GDNF- and FGF10-dependent spreading, proliferation and signaling on LM-511. Thus, our study shows that α3 and α6 containing integrins promote distinct functions and signaling by CD cells on laminin substrata. •Kidney epithelial collecting duct cells that lack both the α3 and α6 integrin subunits were generated.•Deleting both integrin subunits impaired cell adhesion and migration to laminins 332 and 511 more than deleting α3 or α6 alone.•Cell adhesion mediated by α3β1 and α6 integrins was PI3K independent, but required K63-linked polyubiquitination of Akt.•Growth factor-induced signaling, spreading and proliferation was compromised in integrin α3/α6- but not α3- or α6-null cells.•Growth factor-dependent cell functions required both PI3K- and K63-linked polyubiquitination of Akt.