title: PTPN14 forms a complex with Kibra and LATS1 proteins and negatively regulates the YAP oncogenic function.
abstract: The Hippo signaling pathway regulates cellular proliferation and survival, thus exerting profound effects on normal cell fate and tumorigenesis. Pivotal effectors of this pathway are YAP/TAZ, transcriptional co-activators whose dysfunction contributes to epithelial-to-mesenchymal transition and malignant transformation. Therefore, it is of great importance to decipher the mechanisms underlying the regulations of YAP/TAZ at various levels. Here we report that non-receptor tyrosine phosphatase 14 (PTPN14) interacts with the Kibra protein. The interaction between PTPN14 and Kibra is through the PPXY domain of PTPN14 and WW domain of Kibra. PTPN14 and Kibra can induce the LATS1 activation independently and cooperatively. Interestingly, activation of LATS1 by PTPN14 is dependent on the C terminus of PTPN14 and independent of the upstream mammalian STE20-like kinase (MST) proteins. Furthermore, we demonstrate that PTPN14 increases the LAST1 protein stability. Last, overexpression of Kibra rescues the increased cell migration and aberrant three-dimensional morphogenesis induced by knockdown of PTPN14, and this rescue is mediated through the activation of the upstream LATS1 kinase and subsequent cytoplasmic sequestration of YAP. In summary, our results indicate a potential regulatory role of PTPN14 in the Hippo pathway and demonstrate another layer of regulation in the YAP oncogenic function.
authors.affiliation: From the Departments of Cancer Genetics and.
authors.forename: Kayla E
authors.initials: KE
authors.lastname: Wilson
authors.affiliation: From the Departments of Cancer Genetics and.
authors.forename: Ying-Wei
authors.initials: YW
authors.lastname: Li
authors.affiliation: From the Departments of Cancer Genetics and.
authors.forename: Nuo
authors.initials: N
authors.lastname: Yang
authors.affiliation: From the Departments of Cancer Genetics and.
authors.forename: He
authors.initials: H
authors.lastname: Shen
authors.affiliation: Medicine, Roswell Park Cancer Institute, Buffalo, New York 14263.
authors.forename: Ashley R
authors.initials: AR
authors.lastname: Orillion
authors.affiliation: From the Departments of Cancer Genetics and jianmin.zhang@roswellpark.org.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D001483:Base Sequence; D002460:Cell Line; D055785:Gene Knockdown Techniques; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D010750:Phosphoproteins / Q000378:metabolism* / Q000502:physiology*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D014157:Transcription Factors; C513637:WWC1 protein, human; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases; C093261:PTPN14 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor
keywords: Cancer; Cell Migration; Epithelial-Mesenchymal Transition (EMT); Protein Phosphatase; Protein-Protein Interaction