title: Expression of FLNa in human melanoma cells regulates the function of integrin α1β1 and phosphorylation and localisation of PKB/AKT/ERK1/2 kinases.
abstract: FLNa is a ubiquitous cytoskeletal protein that links transmembrane receptors, including integrins, to F-actin and functions as a signalling intermediate. We investigated FLNa's role in the function of integrin-type collagen receptors, EGF-EGFR signalling and regulation of PKB/Akt and ERK1/2. Using FLNa-deficient M2 human melanoma cells, and same cells expressing EGFP-FLNa (M2F) or its Ig-like repeats 1-8+24, 8-15+24 and 16-24, we found that in M2F and M2 8-15+24 cells, EGF induced the increased phosphorylation of PKB/Akt and ERK1/2. In M2F cells EGF induced the localisation of these kinases to cell nucleus and lamellipodia, respectively, and the ERK1/2 phosphorylation-dependent co-immunoprecipitation of FLNa with ERK1/2. Only M2F and M2 8-15+24 cells adhered to and spread on type I collagen whereas on fibronectin all cells behaved similarly. α1β1 and α2β1 were the integrin-type collagen receptors expressed on these cells with primarily α1β1 localising to focal contacts and affecting cell adhesion and migration in a manner dependent on FLNa or its Ig-like repeats 8-15. Our results suggest a role for FLNa repeats 8-15 in the α1-subunit-dependent regulation of integrin α1β1 function, EGF-EGFR signalling to PKB/Akt and ERK1/2, identify ERK1/2 in EGF-induced FLNa-associated protein complexes, and show that the function of different integrins is subjected to differential regulation by FLNa.
authors.affiliation: Institute of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia.
authors.forename: Kristi
authors.initials: K
authors.lastname: Krebs
authors.affiliation: Institute of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia.
authors.forename: Anu
authors.initials: A
authors.lastname: Ruusmann
authors.affiliation: Institute of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia.
authors.forename: Grethel
authors.initials: G
authors.lastname: Simonlatser
authors.affiliation: Institute of Gene Technology, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia. Electronic address: teet.velling@ttu.ee.
authors.forename: Teet
authors.initials: T
authors.lastname: Velling
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D004815:Epidermal Growth Factor / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D064448:Filamins / Q000378:metabolism*; D006801:Humans; D039222:Integrin alpha1beta1 / Q000502:physiology*; D008545:Melanoma / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: C578663:FLNA protein, human; D064448:Filamins; D039222:Integrin alpha1beta1; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: ERK1/2; Filamin A; Integrin; PKB/Akt