title: beta1 integrin/FAK/ERK signalling pathway is essential for human fetal islet cell differentiation and survival.
abstract: beta1 integrin and collagen matrix interactions regulate the survival of cells by associating with focal adhesion kinase (FAK) and initiating MAPK/ERK signalling, but little is known about these signalling pathways during human fetal islet ontogeny. The purpose of this study was to investigate whether beta1 integrin/FAK activation of the MAPK/ERK pathway regulates human fetal islet cell expression of endocrine cell markers and survival. Isolated human (18-21 weeks fetal age) islet-epithelial cell clusters, cultured on collagen I, were examined using beta1 integrin blocking antibody, beta1 integrin siRNA and FAK expression vector. Perturbing beta1 integrin function in the human fetal islet-epithelial cell clusters resulted in a marked decrease in cell adhesion, in parallel with a reduction in the number of cells expressing PDX-1, insulin and glucagon (p < 0.05). beta1 integrin blockade disorganized focal adhesion contacts in the PDX-1(+) cells and decreased activation of FAK and ERK1/2 signalling in parallel with an increase in expression of cleaved caspases 9 and 3 (p < 0.01). Similar results were obtained following an siRNA knock-down of beta1 integrin expression. In contrast, over-expression of FAK not only increased phospho-ERK and the expression of PDX-1, insulin and glucagon (p < 0.05) but also abrogated the decreases in phospho-ERK and PDX-1 by beta1 integrin blockade. This study demonstrates that activation of the FAK/ERK signalling cascade by beta1 integrin is involved in the differentiation and survival of human fetal pancreatic islet cells.
authors: Department of Physiology and Pharmacology, University of Western Ontario, London, Canada.
authors: Saira
authors: S
authors: Saleem
authors: Jinming
authors: J
authors: Li
authors: Siu-Pok
authors: SP
authors: Yee
authors: George F
authors: GF
authors: Fellows
authors: Cynthia G
authors: CG
authors: Goodyer
authors: Rennian
authors: R
authors: Wang
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000166:cytology; D047109:Fetal Development / Q000502:physiology; D051417:Focal Adhesion Kinase 1 / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006801:Humans; D019012:Integrin beta1 / Q000235:genetics / Q000502:physiology*; D007515:Islets of Langerhans / Q000166:cytology / Q000196:embryology*; D020935:MAP Kinase Signaling System / Q000502:physiology*
chemical_list: D019012:Integrin beta1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human