title: α6 integrin transactivates insulin-like growth factor receptor-1 (IGF-1R) to regulate caspase-3-mediated lens epithelial cell differentiation initiation.
abstract: The canonical mitochondrial death pathway was first discovered for its role in signaling apoptosis. It has since been found to have a requisite function in differentiation initiation in many cell types including the lens through low level activation of the caspase-3 protease. The ability of this pathway to function as a molecular switch in lens differentiation depends on the concurrent induction of survival molecules in the Bcl-2 and IAP families, induced downstream of an IGF-1R/NFκB coordinate survival signal, to regulate caspase-3 activity. Here we investigated whether α6 integrin signals upstream to this IGF-1R-mediated survival-linked differentiation signal. Our findings show that IGF-1R is recruited to and activated specifically in α6 integrin receptor signaling complexes in the lens equatorial region, where lens epithelial cells initiate their differentiation program. In studies with both α6 integrin knock-out mice lenses and primary lens cell cultures following α6 integrin siRNA knockdown, we show that IGF-1R activation is dependent on α6 integrin and that this transactivation requires Src kinase activity. In addition, without α6 integrin, activation and expression of NFκB was diminished, and expression of Bcl-2 and IAP family members were down-regulated, resulting in high levels of caspase-3 activation. As a result, a number of hallmarks of lens differentiation failed to be induced; including nuclear translocation of Prox1 in the differentiation initiation zone and apoptosis was promoted. We conclude that α6 integrin is an essential upstream regulator of the IGF-1R survival pathway that regulates the activity level of caspase-3 for it to signal differentiation initiation of lens epithelial cells.
authors.affiliation: From the Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and.
authors.forename: Subhasree
authors.initials: S
authors.lastname: Basu
authors.forename: Suren
authors.initials: S
authors.lastname: Rajakaruna
authors.forename: Adèle
authors.initials: A
authors.lastname: De Arcangelis
authors.forename: Liping
authors.initials: L
authors.lastname: Zhang
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Georges-Labouesse
authors.forename: A Sue
authors.initials: AS
authors.lastname: Menko
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002642:Chick Embryo; D004789:Enzyme Activation / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D039503:Integrin alpha6 / Q000235:genetics / Q000378:metabolism*; D007903:Lens Capsule, Crystalline / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000502:physiology; D015533:Transcriptional Activation / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D051034:Inhibitor of Apoptosis Proteins; D039503:Integrin alpha6; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D050794:STAT1 Transcription Factor; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D017526:Receptor, IGF Type 1; D019061:src-Family Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: Cell Differentiation; Development; Integrins; Lens; Signal Transduction