Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.
Mutations in G protein β subunits promote transformation and kinase inhibitor resistance.
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作者：
G蛋白α亚基（Gα）的激活突变发生在所有人类癌症的4-5%中，但β亚基（Gβ）的致癌性改变尚未确定。在这里，我们证明了Gβ蛋白GNB 1和GNB 2中的复发性突变赋予了非依赖于精氨酸的生长并激活了经典的G蛋白信号传导。GNB 1中的多个突变影响结合Gα亚基以及下游效应物的蛋白质界面，并破坏Gα-Gβγ相互作用。Gβ蛋白中的不同突变在一定程度上基于谱系聚集;例如，所有11个GNB 1 K57突变均发生在髓样肿瘤中，而8个GNB 1 I80突变中有7个发生在B细胞肿瘤中。在Cdkn 2a缺陷型骨髓中表达患者来源的GNB 1等位基因，随后进行移植，导致髓系或B细胞恶性肿瘤。在体内用双重PI 3 K/mTOR抑制剂BEZ 235治疗抑制GNB 1诱导的信号传导并显著增加存活。在几种人类肿瘤中，GNB 1突变与致癌激酶改变同时发生，包括BCR/ABL、JAK 2 V617 F和BRAF V600 K。患者来源的GNB 1等位基因与这些突变激酶的共表达导致了每种情况下的抑制剂耐药性。因此，GNB 1和GNB 2突变在一系列人类肿瘤中赋予转化和抗性表型，并且可以用G蛋白信号传导的抑制剂靶向。
Activating mutations of G protein alpha subunits (Gα) occur in 4–5% of all human cancers but oncogenic alterations in beta subunits (Gβ) have not been defined. Here we demonstrate that recurrent mutations in the Gβ proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Gα subunits as well as downstream effectors, and disrupt Gα-Gβγ interactions. Different mutations in Gβ proteins clustered to some extent based on lineage; for example, all eleven GNB1 K57 mutations were in myeloid neoplasms while 7 of 8 GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 alleles in Cdkn2a-deficient bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K/mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, GNB1 mutations co-occurred with oncogenic kinase alterations, including BCR/ABL, JAK2 V617F and BRAF V600K. Co-expression of patient-derived GNB1 alleles with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 mutations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.
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影响因子：
11.4
作者：
通讯作者：
--
DOI：
10.1126/science.1226344
发表时间：
2012-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iyer G;Hanrahan AJ;Milowsky MI;Al-Ahmadie H;Scott SN;Janakiraman M;Pirun M;Sander C;Socci ND;Ostrovnaya I;Viale A;Heguy A;Peng L;Chan TA;Bochner B;Bajorin DF;Berger MF;Taylor BS;Solit DB
通讯作者：
Solit DB
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
7
作者：
Adelmant, Guillaume;Calkins, Anne S.;Lazaro, Jean-Bernard
通讯作者：
Lazaro, Jean-Bernard
影响因子：
20.3
作者：
Lucioni, Marco;Novara, Francesca;Berti, Emilio
通讯作者：
Berti, Emilio