title: p140Cap suppresses the invasive properties of highly metastatic MTLn3-EGFR cells via impaired cortactin phosphorylation.
abstract: We have recently shown that the adaptor protein p140Cap regulates tumor properties in terms of cell motility and growth. Here, by using the highly metastatic rat adenocarcinoma cell line MTLn3-epidermal growth factor receptor (EGFR), we assess the role of p140Cap in metastasis formation. Orthotopic transplantation of MTLn3-EGFR cells over-expressing p140Cap in Rag2(-/-)γ(c)(-/-) mice resulted in normal primary tumor growth compared with the controls. Strikingly, p140Cap over-expression causes an 80% inhibition in the number of lung metastases. p140Cap over-expressing cells display a 50% reduction in directional cell migration, an increased number and size of focal adhesions, and a strong impairment in the ability to invade in a 3D matrix. p140Cap over-expression affects EGFR signaling and tyrosine phosphorylation of cortactin in response to EGF stimulation. Intriguingly, p140Cap associates with cortactin via interaction with its second proline-rich domain to the cortactin SH3 domain. The phosphomimetic cortactin tyrosine 421 mutant rescues migration and invasive properties in p140Cap over-expressing cells. Taken together, these data demonstrate that p140Cap suppresses the invasive properties of highly metastatic breast carcinoma cells by inhibiting cortactin-dependent cell motility.
authors: Molecular Biotechnology Centre, Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.
authors: L
authors: L
authors: Damiano
authors: S E
authors: SE
authors: Le Dévédec
authors: P
authors: P
authors: Di Stefano
authors: D
authors: D
authors: Repetto
authors: R
authors: R
authors: Lalai
authors: H
authors: H
authors: Truong
authors: J L
authors: JL
authors: Xiong
authors: E H
authors: EH
authors: Danen
authors: K
authors: K
authors: Yan
authors: F J
authors: FJ
authors: Verbeek
authors: E
authors: E
authors: De Luca
authors: F
authors: F
authors: Attanasio
authors: R
authors: R
authors: Buccione
authors: E
authors: E
authors: Turco
authors: B
authors: B
authors: van de Water
authors: P
authors: P
authors: Defilippi
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D051356:Cortactin / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D036641:Microscopy, Fluorescence, Multiphoton; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D051381:Rats; D014183:Transplantation, Heterologous
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D051356:Cortactin; C000631270:Srcin1 protein, rat; D049452:Green Fluorescent Proteins; D004815:Epidermal Growth Factor; C483803:Egfr protein, rat; D066246:ErbB Receptors