title: Tensin2 reduces intracellular phosphatidylinositol 3,4,5-trisphosphate levels at the plasma membrane.
abstract: Tensins are proposed cytoskeleton-regulating proteins. However, Tensin2 additionally inhibits Akt signalling and cell survival. Structural modelling of the Tensin2 phosphatase (PTPase) domain revealed an active site-like pocket receptive towards phosphoinositides. Tensin2-expressing HEK293 cells displayed negligible levels of plasma membrane phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) under confocal microscopy. However, mock-transfected cells, and Tensin2 cells harbouring a putative phosphatase-inactivating mutation, exhibited significant PtdIns(3,4,5)P(3) levels, which decreased upon phosphatidylinositol 3-kinase inhibition with LY294002. In contrast, wtTensin3, mock and mutant cells were identical in membrane PtdIns(3,4,5)P(3) and Akt phosphorylation. In vitro lipid PTPase activity was however undetectable in isolated recombinant PTPase domains of both Tensins, indicating a possible loss of structural stability when expressed in isolation. In summary, we provide evidence that Tensin2, in addition to regulating cytoskeletal dynamics, influences phosphoinositide-Akt signalling through its PTPase domain.
authors.affiliation: Lund University, Department of Laboratory Medicine, Section for Clinical Chemistry, University Hospital Malmö, SE-205 02 Malmö, Sweden. sassan.hafizi@port.ac.uk
authors.forename: Sassan
authors.initials: S
authors.lastname: Hafizi
authors.forename: Anna
authors.initials: A
authors.lastname: Gustafsson
authors.forename: Cecilia
authors.initials: C
authors.lastname: Oslakovic
authors.forename: Olof
authors.initials: O
authors.lastname: Idevall-Hagren
authors.forename: Anders
authors.initials: A
authors.lastname: Tengholm
authors.forename: Olivier
authors.initials: O
authors.lastname: Sperandio
authors.forename: Bruno O
authors.initials: BO
authors.lastname: Villoutreix
authors.forename: Björn
authors.initials: B
authors.lastname: Dahlbäck
mesh_terms: D000595:Amino Acid Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000070876:Tensins
chemical_list: D008840:Microfilament Proteins; D018129:Phosphatidylinositol Phosphates; D011994:Recombinant Proteins; D000070876:Tensins; C060974:phosphatidylinositol 3,4,5-triphosphate; D051057:Proto-Oncogene Proteins c-akt; C452816:TNS2 protein, human; D010744:Phosphoric Monoester Hydrolases