title: PYK2 sustains endosomal-derived receptor signalling and enhances epithelial-to-mesenchymal transition.
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.
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Nandini
authors: N
authors: Verma
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Omer
authors: O
authors: Keinan
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Michael
authors: M
authors: Selitrennik
authors: Department of Obstetrics and Gynecology, Goethe University Frankfurt, Theodor-Stern Kai 7, 60590 Frankfurt, Germany.
authors: Thomas
authors: T
authors: Karn
authors: Clinical Division of Oncology, Department of Medicine I, University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors: Martin
authors: M
authors: Filipits
authors: Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Sima
authors: S
authors: Lev
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D011992:Endosomes / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics / Q000502:physiology*; D051418:Focal Adhesion Kinase 2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
chemical_list: D050796:STAT3 Transcription Factor; D019859:Proto-Oncogene Proteins c-met; D051418:Focal Adhesion Kinase 2