TY - JOUR
T1 - Frequent somatic mutations in MAP3K5 and MAP3K9 in metastatic melanoma identified by exome sequencing
AU - Stark, Mitchell S.
AU - Woods, Susan L.
AU - Gartside, Michael G.
AU - Bonazzi, Vanessa F.
AU - Dutton-Regester, Ken
AU - Aoude, Lauren G.
AU - Chow, Donald
AU - Sereduk, Chris
AU - Niemi, Natalie M.
AU - Tang, Nanyun
AU - Ellis, Jonathan J.
AU - Reid, Jeffrey
AU - Zismann, Victoria
AU - Tyagi, Sonika
AU - Muzny, Donna
AU - Newsham, Irene
AU - Wu, Yuanqing
AU - Palmer, Jane M.
AU - Pollak, Thomas
AU - Youngkin, David
AU - Brooks, Bradford R.
AU - Lanagan, Catherine
AU - Schmidt, Christopher W.
AU - Kobe, Bostjan
AU - MacKeigan, Jeffrey P.
AU - Yin, Hongwei
AU - Brown, Kevin M.
AU - Gibbs, Richard
AU - Trent, Jeffrey
AU - Hayward, Nicholas K.
N1 - Funding Information:
The authors would like to acknowledge M. Aziz for data processing, M. Kassner for technical support and J.-C. Deza for graphics support. This work was funded through grants from the National Health and Medical Research Council of Australia, the Australian Centre for Vaccine Development, the US National Cancer Institute (5U01CA129447 to J.T.), the US National Cancer Institute, Division of Cancer Epidemiology and Genetics (to K.M.B.), and a charitable donation by Francis Najafi (to K.M.B. and J.T.).
PY - 2012/2
Y1 - 2012/2
N2 - We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.
AB - We sequenced eight melanoma exomes to identify new somatic mutations in metastatic melanoma. Focusing on the mitogen-activated protein (MAP) kinase kinase kinase (MAP3K) family, we found that 24% of melanoma cell lines have mutations in the protein-coding regions of either MAP3K5 or MAP3K9. Structural modeling predicted that mutations in the kinase domain may affect the activity and regulation of these protein kinases. The position of the mutations and the loss of heterozygosity of MAP3K5 and MAP3K9 in 85% and 67% of melanoma samples, respectively, together suggest that the mutations are likely to be inactivating. In in vitro kinase assays, MAP3K5 I780F and MAP3K9 W333* variants had reduced kinase activity. Overexpression of MAP3K5 or MAP3K9 mutants in HEK293T cells reduced the phosphorylation of downstream MAP kinases. Attenuation of MAP3K9 function in melanoma cells using siRNA led to increased cell viability after temozolomide treatment, suggesting that decreased MAP3K pathway activity can lead to chemoresistance in melanoma.
UR - http://www.scopus.com/inward/record.url?scp=84856273432&partnerID=8YFLogxK
U2 - 10.1038/ng.1041
DO - 10.1038/ng.1041
M3 - Article
C2 - 22197930
AN - SCOPUS:84856273432
VL - 44
SP - 165
EP - 169
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 2
ER -