title: Subcellular compartmentalization of docking protein-1 contributes to progression in colorectal cancer.
abstract: Full-length (FL) docking protein-1 (DOK1) is an adapter protein which inhibits growth factor and immune response pathways in normal tissues, but is frequently lost in human cancers. Small DOK1 variants remain in cells of solid tumors and leukemias, albeit, their functions are elusive. To assess the so far unknown role of DOK1 in colorectal cancer (CRC), we generated DOK1 mutants which mimic the domain structure and subcellular distribution of DOK1 protein variants in leukemia patients. We found that cytoplasmic DOK1 activated peroxisome-proliferator-activated-receptor-gamma (PPARγ) resulting in inhibition of the c-FOS promoter and cell proliferation, whereas nuclear DOK1 was inactive. PPARγ-agonist increased expression of endogenous DOK1 and interaction with PPARγ. Forward translation of this cell-based signaling model predicted compartmentalization of DOK1 in patients. In a large series of CRC patients, loss of DOK1 protein was associated with poor prognosis at early tumor stages (*p=0.001; n=1492). In tumors with cytoplasmic expression of DOK1, survival was improved, whereas nuclear localization of DOK1 correlated with poor outcome, indicating that compartmentalization of DOK1 is critical for CRC progression. Thus, DOK1 was identified as a prognostic factor for non-metastatic CRC, and, via its drugability by PPARγ-agonist, may constitute a potential target for future cancer treatments.
authors.affiliation: Dept. of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Friedrich
authors.affiliation: Dept. of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Söhn
authors.affiliation: Dept. of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Gutting
authors.affiliation: Dept. of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
authors.affiliation: Institute of Pathology, Christian-Albrechts University, Kiel, Germany.
authors.forename: Hans-Michael
authors.initials: HM
authors.lastname: Behrens
authors.affiliation: Institute of Pathology, Christian-Albrechts University, Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Dept. of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
authors.forename: Matthias P A
authors.initials: MPA
authors.lastname: Ebert
authors.affiliation: Dept. of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: elke.burgermeister@medma.uni-heidelberg.de.
authors.forename: Elke
authors.initials: E
authors.lastname: Burgermeister
mesh_terms: D015415:Biomarkers; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D047495:PPAR gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D015533:Transcriptional Activation
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; C489560:DOK1 protein, human; D008024:Ligands; D047495:PPAR gamma; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D016601:RNA-Binding Proteins
keywords: Colorectal cancer; DOK; Docking protein; PPAR; RAS