Article open access publication

A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation

Oncogene, Springer Nature, ISSN 0950-9232

Volume 35, 33, 2016

DOI:10.1038/onc.2015.504, Dimensions: pub.1043263135, PMC: PMC4994017, PMID: 26804170,


Grassilli, E * (1) (2)
Pisano, F (1) (2)
Cialdella, A (1) (2)
Bonomo, S (2)
Noli, B (3)
Stanta, G (4)
Bonin, S (4)
Helin, K (5)
Lavitrano, M * (2)

* Corresponding author



  1. (1) BiOnSil srl, Monza, Italy
  2. (2) University of Milano-Bicocca, grid.7563.7
  3. (3) University of Cagliari, grid.7763.5
  4. (4) Department of Medical Sciences, University of Trieste, Cattinara Hospital, Trieste, Italy
  5. (5) University of Copenhagen, grid.5254.6, KU







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.


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