PYK2 sustains endosomal-derived receptor signalling and enhances epithelial-to-mesenchymal transition

Nat Commun. 2015 Feb 4;6:6064. doi: 10.1038/ncomms7064.

Abstract

Epithelial-to-mesenchymal transition (EMT) is a central developmental process implicated in cancer metastasis. Here we show that the tyrosine kinase PYK2 enhances cell migration and invasion and potentiates EMT in human breast carcinoma. EMT inducer, such as EGF, induces rapid phosphorylation of PYK2 and its translocation to early endosomes where it co-localizes with EGFR and sustains its downstream signals. Furthermore, PYK2 enhances EGF-induced STAT3-phosphorylation, while phospho-STAT3 directly binds to PYK2 promoter and regulates PYK2 transcription. STAT3 and PYK2 also enhance c-Met expression, while c-Met augments their phosphorylation, suggesting a positive feedback loop between PYK2-STAT3-c-Met. We propose that PYK2 sustains endosomal-derived receptor signalling and participates in a positive feedback that links cell surface receptor(s) to transcription factor(s) activation, thereby prolonging signalling duration and potentiating EMT. Given the role of EMT in breast cancer metastasis, we also found a significant correlation between PYK2 expression, tumour grade and lymph node metastasis, thus, demonstrating the clinicopathological implication of our findings.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Endosomes / metabolism*
  • Epithelial-Mesenchymal Transition / genetics
  • Epithelial-Mesenchymal Transition / physiology*
  • Focal Adhesion Kinase 2 / genetics
  • Focal Adhesion Kinase 2 / metabolism*
  • Humans
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology

Substances

  • STAT3 Transcription Factor
  • Proto-Oncogene Proteins c-met
  • Focal Adhesion Kinase 2