Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation.
Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate cell transformation.
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DOI：
10.1126/scisignal.aar8371
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发表时间：
2018-09-04
影响因子：
7.3
通讯作者：
Kortum RL
中科院分区：
文献类型：
--
作者：
Sheffels E;Sealover NE;Wang C;Kim DH;Vazirani IA;Lee E;M Terrell E;Morrison DK;Luo J;Kortum RL
About a third of tumors harbor activating mutations in HRAS, NRAS, or KRAS, genes encoding guanine triphosphatases (GTPases) of the RAS family. In these tumors, wild-type RAS signaling cooperates with mutant RAS to promote downstream effector activation. This cooperation between wild-type and mutant RAS drives proliferation and transformation, suggesting that upstream activators of wild-type RAS are important modulators of mutant RAS-driven oncogenesis. Previous studies investigated the role of the guanine nucleotide exchange factor (GEF) SOS1 in KRAS-driven proliferation, but little is understood about the role of SOS2. Here, we found that RAS family members have a hierarchical requirement for SOS2 expression and activity to drive transformation. In Sos2−/− mouse embryonic fibroblasts, SOS2 critically mediated mutant KRAS-driven transformation, but was dispensable for transformation driven by HRAS. Sos2 deletion reduced EGF-dependent wild-type HRAS activation and phosphorylation of the kinase AKT in cells expressing mutant RAS, and assays using pharmacological inhibition revealed a hierarchical requirement for signaling by the kinase PI3K in promoting RAS-driven transformation that mirrored the requirement for SOS2. KRAS-driven transformation required the GEF activity of SOS2 and was restored in Sos2−/− MEFs by expression of constitutively activated PI3K. Finally, CRISPR/Cas9-mediated deletion of SOS2 reduced EGF-stimulated AKT phosphorylation and synergized with MEK inhibition to block transformation of KRAS-mutant tumor cells. These results indicate that SOS2-dependent PI3K signaling plays an important role in mutant KRAS-driven transformation; hence, SOS2 may be a therapeutic target in KRAS-driven cancers. Additionally, our data reveal the importance of 3D-culture systems in investigating important mediators of mutant KRAS.
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DOI：
10.1073/pnas.82.23.7810
发表时间：
1985-01-01
影响因子：
11.1
作者：
GUERRERO, I;VILLASANTE, A;PELLICER, A
通讯作者：
PELLICER, A
影响因子：
16.6
作者：
通讯作者：
--
影响因子：
18.4
作者：
Haigis KM
通讯作者：
Haigis KM
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
通过整合多样化的OMIC数据来重建肺癌中的可靶向途径。
影响因子：
16.6
作者：
Balbin, O. Alejandro;Prensner, John R.;Sahu, Anirban;Yocum, Anastasia;Shankar, Sunita;Malik, Rohit;Fermin, Damian;Dhanasekaran, Saravana M.;Chandler, Benjamin;Thomas, Dafydd;Beer, David G.;Cao, Xuhong;Nesvizhskii, Alexey I.;Chinnaiyan, Arul M.
通讯作者：
Chinnaiyan, Arul M.