N-WASP activation by a beta1-integrin-dependent mechanism supports PI3K-independent chemotaxis stimulated by urokinase-type plasminogen activator.
Urokinase-type plasminogen activator (uPA)-uPA receptor (uPAR) and epidermal growth factor (EGF)-EGF receptor (EGFR) expression is highly correlated with breast cancer metastasis. Phosphoinositide 3-kinase (PI3K), small Rho GTPases, such as Cdc42 and Rac1, and neuronal Wiskott Aldrich syndrome protein (N-WASP) are key effectors that regulate dynamic changes in the actin cytoskeleton and cell migration. uPA- and EGF-stimulated chemotaxis, cytoskeletal rearrangements and activation of Cdc42, Rac1 and N-WASP were studied in the highly metastatic human breast cancer cell line MDA MB 231. These studies reveal that divergent signalling occurs downstream of PI3K. The activity of PI3K was not necessary for uPA-induced chemotactic responses, but those induced by EGF were entirely dependent upon PI3K. Furthermore, PI3K-independent chemotactic signalling by uPA was shown to involve disruption of an interaction between beta(1)-integrins and N-WASP and translocation of N-WASP to the actin cytoskeleton.
Sturge
Justin
J
The Randall Centre for Molecular Mechanisms of Cell Function, New Hunt's House, King's College London, Guy's Campus, London SE1 1UL, UK.
Hamelin
Jocelyne
J
Jones
Gareth E
GE
D000199:Actins / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002633:Chemotaxis / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D019012:Integrin beta1; D009419:Nerve Tissue Proteins; C495771:WASL protein, human; D051317:Wiskott-Aldrich Syndrome Protein, Neuronal; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D014568:Urokinase-Type Plasminogen Activator; D020741:rho GTP-Binding Proteins