title: PTK6 activation at the membrane regulates epithelial-mesenchymal transition in prostate cancer.
abstract: The intracellular tyrosine kinase protein tyrosine kinase 6 (PTK6) lacks a membrane-targeting SH4 domain and localizes to the nuclei of normal prostate epithelial cells. However, PTK6 translocates from the nucleus to the cytoplasm in human prostate tumor cells. Here, we show that while PTK6 is located primarily within the cytoplasm, the pool of active PTK6 in prostate cancer cells localizes to membranes. Ectopic expression of membrane-targeted active PTK6 promoted epithelial-mesenchymal transition in part by enhancing activation of AKT, thereby stimulating cancer cell migration and metastases in xenograft models of prostate cancer. Conversely, siRNA-mediated silencing of endogenous PTK6 promoted an epithelial phenotype and impaired tumor xenograft growth. In mice, PTEN deficiency caused endogenous active PTK6 to localize at membranes in association with decreased E-cadherin expression. Active PTK6 was detected at membranes in some high-grade human prostate tumors, and PTK6 and E-cadherin expression levels were inversely correlated in human prostate cancers. In addition, high levels of PTK6 expression predicted poor prognosis in patients with prostate cancer. Our findings reveal novel functions for PTK6 in the pathophysiology of prostate cancer, and they define this kinase as a candidate therapeutic target. Cancer Res; 73(17); 5426-37. ©2013 AACR.
authors.affiliation: Department of Biochemistry, Biopharmaceutical Sciences, and Pathology, University of Illinois at Chicago, Chicago, IL 60607, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.forename: Zebin
authors.initials: Z
authors.lastname: Wang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Bie
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Brauer
authors.forename: Bethany E
authors.initials: BE
authors.lastname: Perez White
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Veronique
authors.initials: V
authors.lastname: Nogueira
authors.forename: Pradip
authors.initials: P
authors.lastname: Raychaudhuri
authors.forename: Nissim
authors.initials: N
authors.lastname: Hay
authors.forename: Debra A
authors.initials: DA
authors.lastname: Tonetti
authors.forename: Virgilia
authors.initials: V
authors.lastname: Macias
authors.forename: André
authors.initials: A
authors.lastname: Kajdacsy-Balla
authors.forename: Angela L
authors.initials: AL
authors.lastname: Tyner
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D047468:Immunoprecipitation; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D015820:Cadherins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse