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

Nandini Verma, Omer Keinan, Michael Selitrennik, Thomas Karn, Martin Filipits and Sima Lev ()
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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

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms7064

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