title: Formin-like 2 Promotes β1-Integrin Trafficking and Invasive Motility Downstream of PKCα.
abstract: Regulated turnover of integrin receptors is essential for cell adhesion and migration. Pathways selectively regulating β1-integrin recycling are implicated in cancer invasion and metastasis, yet proteins required for the internalization of this pro-invasive integrin remain to be identified. Here, we uncover formin-like 2 (FMNL2) as a critical regulator of β1-integrin internalization downstream of protein kinase C (PKC). PKCα associates with and phosphorylates FMNL2 at S1072 within its Diaphanous autoregulatory region, leading to the release of formin autoinhibition. Phosphorylation of FMNL2 triggers its rapid relocation and promotes its interaction with the cytoplasmic tails of the α-integrin subunits for β1-integrin endocytosis. FMNL2 drives β1-integrin internalization and invasive motility in a phosphorylation-dependent manner, while a FMNL2 mutant defective in actin assembly interferes with β1-integrin endocytosis and cancer cell invasion. Our data establish a role for FMNL2 in the regulation of β1-integrin and provide a mechanistic understanding of the function of FMNL2 in cancer invasiveness.
authors.affiliation: Institute of Pharmacology, University of Marburg, 35043 Marburg, Germany.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Turku Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Arjonen
authors.affiliation: Turku Centre for Biotechnology, University of Turku, 20520 Turku, Finland.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Pouwels
authors.affiliation: Department of NanoBiophotonics, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
authors.forename: Haisen
authors.initials: H
authors.lastname: Ta
authors.affiliation: LOEWE Center for Synthetic Microbiology (SYNMIKRO) and Department of Chemistry, University of Marburg, 35043 Marburg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Pausch
authors.affiliation: LOEWE Center for Synthetic Microbiology (SYNMIKRO) and Department of Chemistry, University of Marburg, 35043 Marburg, Germany.
authors.forename: Gert
authors.initials: G
authors.lastname: Bange
authors.affiliation: Nikon Imaging Center and COS, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Engel
authors.affiliation: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Fackler
authors.affiliation: Turku Centre for Biotechnology, University of Turku, 20520 Turku, Finland; Department of Biochemistry and Food Chemistry, University of Turku, 20520 Turku, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ivaska
authors.affiliation: Institute of Pharmacology, University of Marburg, 35043 Marburg, Germany. Electronic address: robert.grosse@staff.uni-marburg.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Grosse
mesh_terms: D000595:Amino Acid Sequence; D002465:Cell Movement; D003593:Cytoplasm / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D004789:Enzyme Activation; D000080865:Formins; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D019012:Integrin beta1 / Q000737:chemistry / Q000378:metabolism*; D007425:Intracellular Membranes / Q000378:metabolism; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*
chemical_list: C476208:FMNL2 protein, human; D000080865:Formins; D019012:Integrin beta1; D011506:Proteins; D010768:Phosphoserine; D051571:Protein Kinase C-alpha