title: c-Src, Insulin-Like Growth Factor I Receptor, G-Protein-Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes.
abstract: It is well known that Src tyrosine kinase, insulin-like growth factor 1 receptor (IGF-IR), and focal adhesion kinase (FAK) play important roles in prostate cancer (PrCa) development and progression. Src, which signals through FAK in response to integrin activation, has been implicated in many aspects of tumor biology, such as cell proliferation, metastasis, and angiogenesis. Furthermore, Src signaling is known to crosstalk with IGF-IR, which also promotes angiogenesis. In this study, we demonstrate that c-Src, IGF-IR, and FAK are packaged into exosomes (Exo), c-Src in particular being highly enriched in Exo from the androgen receptor (AR)-positive cell line C4-2B and AR-negative cell lines PC3 and DU145. Furthermore, we show that the active phosphorylated form of Src (SrcpY416) is co-expressed in Exo with phosphorylated FAK (FAKpY861), a known target site of Src, which enhances proliferation and migration. We further demonstrate for the first time exosomal enrichment of G-protein-coupled receptor kinase (GRK) 5 and GRK6, both of which regulate Src and IGF-IR signaling and have been implicated in cancer. Finally, SrcpY416and c-Src are both expressed in Exo isolated from the plasma of prostate tumor-bearing TRAMP mice, and those same mice have higher levels of exosomal c-Src than their wild-type counterparts. In summary, we provide new evidence that active signaling molecules relevant to PrCa are enriched in Exo, and this suggests that the Src signaling network may provide useful biomarkers detectable by liquid biopsy, and may contribute to PrCa progression via Exo. J. Cell. Biochem. 118: 66-73, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Prostate Cancer Discovery and Development Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: DeRita
authors.affiliation: Prostate Cancer Discovery and Development Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Brad
authors.initials: B
authors.lastname: Zerlanko
authors.affiliation: Prostate Cancer Discovery and Development Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Amrita
authors.initials: A
authors.lastname: Singh
authors.affiliation: Prostate Cancer Discovery and Development Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Huimin
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Renato V
authors.initials: RV
authors.lastname: Iozzo
authors.affiliation: Departments of Biochemistry and Molecular Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Benovic
authors.affiliation: Prostate Cancer Discovery and Development Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.|Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D055354:Exosomes / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism*; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism*; D054768:G-Protein-Coupled Receptor Kinases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1; D000081247:CSK Tyrosine-Protein Kinase; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D019061:src-Family Kinases; C000631346:CSK protein, human; D054774:G-Protein-Coupled Receptor Kinase 5; D054768:G-Protein-Coupled Receptor Kinases; C089176:G-protein-coupled receptor kinase 6; C517898:GRK5 protein, human
keywords: EXOSOMES; FOCAL ADHESION KINASE; G-PROTEIN-COUPLED RECEPTOR KINASE; PROSTATE CANCER; SIGNALING; Src; VESICLES