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c-erbB2-induced disruption of matrix adhesion and morphogenesis reveals a novel role for protein kinase B as a negative regulator of alpha(2)beta(1) integrin function.

Författare och institution:
Lachmi E Lindberg (Institutionen för medicinsk och fysiologisk kemi); Shahram Hedjazifar (Institutionen för medicinsk och fysiologisk kemi); Dan Baeckström (Institutionen för medicinsk och fysiologisk kemi)
Publicerad i:
Molecular biology of the cell, 13 ( 8 ) s. 2894-908
Artikel, refereegranskad vetenskaplig
Sammanfattning (abstract):
Overexpression of the growth factor receptor subunit c-erbB2, leading to its ligand-independent homodimerization and activation, has been implicated in the pathogenesis of mammary carcinoma. Here, we have examined the effects of c-erbB2 on the adhesive properties of a mammary epithelial cell line, HB2/tnz34, in which c-erbB2 homodimerization can be induced by means of a transfected hybrid "trk-neu" construct. trk-neu consists of the extracellular domain of the trkA nerve growth factor (NGF) receptor fused to the transmembrane and cytoplasmic domains of c-erbB2, allowing NGF-induced c-erbB2 homodimer signaling. Both spreading and adhesion on collagen surfaces were impaired on c-erbB2 activation in HB2/tnz34 cells. Antibody-mediated stimulation of alpha(2)beta(1) integrin function restored adhesion, suggesting a direct role for c-erbB2 in integrin inactivation. Using pharmacological inhibitors and transient transfections, we identified signaling pathways required for suppression of integrin function by c-erbB2. Among these was the MEK-ERK pathway, previously implicated in integrin inactivation. However, we could also show that downstream of phosphoinositide-3-kinase (PI3K), protein kinase B (PKB) acted as a previously unknown, potent inhibitor of integrin function and mediator of the disruptive effects of c-erbB2 on adhesion and morphogenesis. The integrin-linked kinase, previously identified as a PKB coactivator, was also found to be required for integrin inactivation by c-erbB2. In addition, the PI3K-dependent mTOR/S6 kinase pathway was shown to mediate c-erbB2-induced inhibition of adhesion (but not spreading) independently of PKB. Overexpression of MEK1 or PKB suppressed adhesion without requirement for c-erbB2 activation, suggesting that these two pathways partake in integrin inhibition by targeting common downstream effectors. These results demonstrate a major novel role for PI3K and PKB in regulation of integrin function.
Ämne (baseras på Högskoleverkets indelning av forskningsämnen):
1-Phosphatidylinositol 3-Kinase, metabolism, Animals, Cell Adhesion, physiology, Cell Line, Collagen Type I, metabolism, Dimerization, Enzyme Activation, Enzyme Inhibitors, pharmacology, Epithelial Cells, cytology, drug effects, metabolism, Extracellular Matrix, metabolism, Female, Genes, Reporter, Humans, Integrin alpha2beta1, metabolism, MAP Kinase Signaling System, physiology, Mammary Glands, Animal, cytology, Mitogen-Activated Protein Kinases, metabolism, Morphogenesis, Nerve Growth Factor, pharmacology, Protein Kinases, metabolism, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, metabolism, Proto-Oncogene Proteins c-akt, Receptor, erbB-2, genetics, metabolism, Receptor, trkA, genetics, metabolism, Recombinant Fusion Proteins, genetics, metabolism, Sirolimus, pharmacology
Postens nummer:
Posten skapad:
2007-11-12 10:22
Posten ändrad:
2011-01-20 09:58

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