title: Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells.
abstract: BACKGROUND
  The Src tyrosine kinase substrate and adaptor protein Tks5 had previously been implicated in the invasive phenotype of normal and transformed cell types via regulation of cytoskeletal structures called podosomes/invadopodia. The role of Src-Tks5 signaling in invasive prostate cancer, however, had not been previously evaluated.
  
  
  METHODS
  We measured the relative expression of Tks5 in normal (n = 20) and cancerous (n = 184, from 92 patients) prostate tissue specimens by immunohistochemistry using a commercially available tumor microarray. We also manipulated the expression and activity of wild-type and mutant Src and Tks5 constructs in the LNCaP and PC-3 prostate cancer cell lines in order to ascertain the role of Src-Tks5 signaling in invadopodia development, matrix-remodeling activity, motility, and invasion.
  
  
  RESULTS
  Our studies demonstrated that Src was activated and Tks5 upregulated in high Gleason score prostate tumor specimens and in invasive prostate cancer cell lines. Remarkably, overexpression of Tks5 in LNCaP cells was sufficient to induce invadopodia formation and associated matrix degradation. This Tks5-dependent increase in invasive behavior further depended on Src tyrosine kinase activity and the phosphorylation of Tks5 at tyrosine residues 557 and 619. In PC-3 cells we demonstrated that Tks5 phosphorylation at these sites was necessary and sufficient for invadopodia-associated matrix degradation and invasion.
  
  
  CONCLUSIONS
  Our results suggest a general role for Src-Tks5 signaling in prostate tumor progression and the utility of Tks5 as a marker protein for the staging of this disease.
authors.affiliation: Department of Cancer Biology, Wake Forest Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Burger
authors.forename: Brian S
authors.initials: BS
authors.lastname: Learman
authors.forename: Amy K
authors.initials: AK
authors.lastname: Boucherle
authors.forename: S Joseph
authors.initials: SJ
authors.lastname: Sirintrapun
authors.forename: Scott
authors.initials: S
authors.lastname: Isom
authors.forename: Begoña
authors.initials: B
authors.lastname: Díaz
authors.forename: Sara A
authors.initials: SA
authors.lastname: Courtneidge
authors.forename: Darren F
authors.initials: DF
authors.lastname: Seals
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000502:physiology*; D000230:Adenocarcinoma / Q000473:pathology* / Q000503:physiopathology; D014408:Biomarkers, Tumor / Q000502:physiology; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D003599:Cytoskeleton / Q000502:physiology*; D018450:Disease Progression; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D010766:Phosphorylation / Q000502:physiology; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D014408:Biomarkers, Tumor; C478582:SH3PXD2A protein, human; D019061:src-Family Kinases
keywords: biomarker; cytoskeleton; metastasis; motility; podosome