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

Author

Listed:
  • Nandini Verma

    (Weizmann Institute of Science)

  • Omer Keinan

    (Weizmann Institute of Science)

  • Michael Selitrennik

    (Weizmann Institute of Science)

  • Thomas Karn

    (Goethe University Frankfurt)

  • Martin Filipits

    (University of Vienna)

  • Sima Lev

    (Weizmann Institute of Science)

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.

Suggested Citation

  • Nandini Verma & Omer Keinan & Michael Selitrennik & Thomas Karn & Martin Filipits & Sima Lev, 2015. "PYK2 sustains endosomal-derived receptor signalling and enhances epithelial-to-mesenchymal transition," Nature Communications, Nature, vol. 6(1), pages 1-14, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7064
    DOI: 10.1038/ncomms7064
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    Cited by:

    1. Seyedeh Fatemeh Razavipour & Hyunho Yoon & Kibeom Jang & Minsoon Kim & Hend M. Nawara & Amir Bagheri & Wei-Chi Huang & Miyoung Shin & Dekuang Zhao & Zhiqun Zhou & Derek Boven & Karoline Briegel & Llui, 2024. "C-terminally phosphorylated p27 activates self-renewal driver genes to program cancer stem cell expansion, mammary hyperplasia and cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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