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.

journal_name

Oncogene

journal_title

Oncogene

authors

Grassilli E,Pisano F,Cialdella A,Bonomo S,Missaglia C,Cerrito MG,Masiero L,Ianzano L,Giordano F,Cicirelli V,Narloch R,D'Amato F,Noli B,Ferri GL,Leone BE,Stanta G,Bonin S,Helin K,Giovannoni R,Lavitrano M

doi

10.1038/onc.2015.504

subject

Has Abstract

pub_date

2016-08-18 00:00:00

pages

4368-78

issue

33

eissn

0950-9232

issn

1476-5594

pii

onc2015504

journal_volume

35

pub_type

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