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

TY - JOUR

T1 - A novel oncogenic BTK isoform is overexpressed in colon cancers and required for RAS-mediated transformation

AU - Grassilli, E

AU - Pisano, F

AU - Cialdella, A

AU - Bonomo, S

AU - Missaglia, C

AU - Cerrito, M G

AU - Masiero, L

AU - Ianzano, L

AU - Giordano, F

AU - Cicirelli, V

AU - Narloch, R

AU - D'Amato, F

AU - Noli, B

AU - Ferri, G L

AU - Leone, B E

AU - Stanta, G

AU - Bonin, S

AU - Helin, K

AU - Giovannoni, R

AU - Lavitrano, M

PY - 2016/8/18

Y1 - 2016/8/18

N2 - 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.

AB - 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.

U2 - 10.1038/onc.2015.504

DO - 10.1038/onc.2015.504

M3 - Journal article

C2 - 26804170

SN - 0950-9232

VL - 35

SP - 4368

EP - 4378

JO - Oncogene

JF - Oncogene

ER -