Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells

Karen L. Burger, Brian S. Learman, Amy K. Boucherle, S. Joseph Sirintrapun, Scott Isom, Begoña Díaz, Sara Courtneidge, Darren F. Seals

Research output: Contribution to journalArticle

30 Citations (Scopus)

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. Prostate 74:134-148, 2014.

Original languageEnglish (US)
Pages (from-to)134-148
Number of pages15
JournalProstate
Volume74
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Phosphorylation
Prostate
src-Family Kinases
Cell Line
Neoplasms
Neoplasm Grading
Tyrosine
Proteins
Immunohistochemistry
Podosomes
Phenotype

Keywords

  • biomarker
  • cytoskeleton
  • metastasis
  • motility
  • podosome

ASJC Scopus subject areas

  • Urology
  • Oncology

Cite this

Burger, K. L., Learman, B. S., Boucherle, A. K., Sirintrapun, S. J., Isom, S., Díaz, B., ... Seals, D. F. (2014). Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells. Prostate, 74(2), 134-148. https://doi.org/10.1002/pros.22735

Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells. / Burger, Karen L.; Learman, Brian S.; Boucherle, Amy K.; Sirintrapun, S. Joseph; Isom, Scott; Díaz, Begoña; Courtneidge, Sara; Seals, Darren F.

In: Prostate, Vol. 74, No. 2, 02.2014, p. 134-148.

Research output: Contribution to journalArticle

Burger, KL, Learman, BS, Boucherle, AK, Sirintrapun, SJ, Isom, S, Díaz, B, Courtneidge, S & Seals, DF 2014, 'Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells', Prostate, vol. 74, no. 2, pp. 134-148. https://doi.org/10.1002/pros.22735
Burger KL, Learman BS, Boucherle AK, Sirintrapun SJ, Isom S, Díaz B et al. Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells. Prostate. 2014 Feb;74(2):134-148. https://doi.org/10.1002/pros.22735
Burger, Karen L. ; Learman, Brian S. ; Boucherle, Amy K. ; Sirintrapun, S. Joseph ; Isom, Scott ; Díaz, Begoña ; Courtneidge, Sara ; Seals, Darren F. / Src-dependent Tks5 phosphorylation regulates invadopodia-associated invasion in prostate cancer cells. In: Prostate. 2014 ; Vol. 74, No. 2. pp. 134-148.
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AU - Learman, Brian S.

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AU - Sirintrapun, S. Joseph

AU - Isom, Scott

AU - Díaz, Begoña

AU - Courtneidge, Sara

AU - Seals, Darren F.

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N2 - 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. Prostate 74:134-148, 2014.

AB - 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. Prostate 74:134-148, 2014.

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