title: A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation.
abstract: Bruton's tyrosine kinase (BTK) is essential for B-cell proliferation/differentiation and it is generally believed that its expression and function are limited to bone marrow-derived cells. Here, we report the identification and characterization of p65BTK, a novel isoform abundantly expressed in colon carcinoma cell lines and tumour tissue samples. p65BTK protein is expressed, through heterogeneous nuclear ribonucleoprotein K (hnRNPK)-dependent and internal ribosome entry site-driven translation, from a transcript containing an alternative first exon in the 5'-untranslated region, and is post-transcriptionally regulated, via hnRNPK, by the mitogen-activated protein kinase (MAPK) pathway. p65BTK is endowed with strong transforming activity that depends on active signal-regulated protein kinases-1/2 (ERK1/2) and its inhibition abolishes RAS transforming activity. Accordingly, p65BTK overexpression in colon cancer tissues correlates with ERK1/2 activation. Moreover, p65BTK inhibition affects growth and survival of colon cancer cells. Our data reveal that BTK, via p65BTK expression, is a novel and powerful oncogene acting downstream of the RAS/MAPK pathway and suggest that its targeting may be a promising therapeutic approach.
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.|BiOnSil srl, Monza, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Grassilli
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.|BiOnSil srl, Monza, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Pisano
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.|BiOnSil srl, Monza, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cialdella
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bonomo
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Missaglia
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Cerrito
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Masiero
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ianzano
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Giordano
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Cicirelli
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Narloch
authors.affiliation: NEF-Laboratory, Department of Biomedical Science, University of Cagliari, Monserrato, Italy.
authors.forename: F
authors.initials: F
authors.lastname: D'Amato
authors.affiliation: NEF-Laboratory, Department of Biomedical Science, University of Cagliari, Monserrato, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Noli
authors.affiliation: NEF-Laboratory, Department of Biomedical Science, University of Cagliari, Monserrato, Italy.
authors.forename: G L
authors.initials: GL
authors.lastname: Ferri
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: B E
authors.initials: BE
authors.lastname: Leone
authors.affiliation: Department of Medical Sciences, University of Trieste, Cattinara Hospital, Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Stanta
authors.affiliation: Department of Medical Sciences, University of Trieste, Cattinara Hospital, Trieste, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bonin
authors.affiliation: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark.|Center for Epigenetics, University of Copenhagen, Copenhagen, Denmark.|Danish Stem Cell Center (Danstem), University of Copenhagen, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Helin
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Giovannoni
authors.affiliation: School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Lavitrano
mesh_terms: D020121:5' Untranslated Regions / Q000502:physiology; D000077329:Agammaglobulinaemia Tyrosine Kinase; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D034641:Heterogeneous-Nuclear Ribonucleoprotein K / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
chemical_list: D020121:5' Untranslated Regions; D034641:Heterogeneous-Nuclear Ribonucleoprotein K; D020033:Protein Isoforms; C072074:HNRNPK protein, human; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D018631:ras Proteins