ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1.
ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1.
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DOI：
10.1016/j.molcel.2022.04.034
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发表时间：
2022-07-07
期刊：
影响因子：
16
通讯作者：
Rosen, Neal
中科院分区：
文献类型：
--
作者：
Su, Wenjing;Mukherjee, Radha;Yaeger, Rona;Son, Jieun;Xu, Jianing;Na, Na;Timaul, Neilawattie Merna;Hechtman, Jaclyn;Paroder, Viktoriya;Lin, Mika;Mattar, Marissa;Qiu, Juan;Chang, Qing;Zhao, Huiyong;Zhang, Jonathan;Little, Megan;Adachi, Yuta;Han, Sae-Won;Taylor, Barry S.;Ebi, Hiromichi;Abdel-Wahab, Omar;de Stanchina, Elisa;Rudin, Charles M.;Janne, Pasi A.;McCormick, Frank;Yao, Zhan;Rosen, Neal
RAF蛋白激酶是小鸟苷三磷酸酶RAS的GTP结合形式的效应物，并通过磷酸化MEK发挥功能。我们发现ARAF的表达以激酶非依赖性方式激活RAS。ARAF与RAS的结合取代了GTP酶激活蛋白NF 1，并拮抗NF 1介导的RAS抑制。这降低了RAS的ERK依赖性抑制并增加了RAS-GTP。通过这种机制，ARAF调节RTK诱导的RAS激活的持续时间和结果，并支持RTK依赖性肿瘤细胞的RAS输出。在EGFR突变的人肺癌中，ARAF的扩增与EGFR抑制剂的获得性耐药相关，通过将EGFR抑制剂与蛋白酪氨酸磷酸酶SHP 2抑制剂组合以增强核苷酸交换和RAS激活的抑制来克服。Su等揭示了ARAF通过拮抗其与NF 1 RAS-GAP的结合来激活RAS。通过这种机制，ARAF的丰度决定了RAS-GTP水平以及RAS信号转导的RTK激活的持续时间和生物学后果。此外，ARAF扩增导致肺癌对EGFR抑制的抗性。
RAF protein kinases are effectors of the GTP-bound form of the small guanosine triphosphatase RAS and function by phosphorylating MEK. We showed here that expression of ARAF activated RAS in a kinase-independent manner. Binding of ARAF to RAS displaced the GTPase-activating protein NF1 and antagonized NF1-mediated inhibition of RAS. This reduced ERK-dependent inhibition of RAS and increased RAS-GTP. By this mechanism, ARAF regulated the duration and consequences of RTK-induced RAS activation and supported the RAS output of RTK-dependent tumor cells. In human lung cancers with EGFR mutation, amplification of ARAF was associated with acquired resistance to EGFR inhibitors, which was overcome by combining EGFR inhibitors with an inhibitor of the protein tyrosine phosphatase SHP2 to enhance inhibition of nucleotide exchange and RAS activation. Su et al. reveal that ARAF activates RAS by antagonizing its binding to the NF1 RAS-GAP. By this mechanism, the abundance of ARAF determines RAS-GTP levels and the duration and biologic consequences of RTK-activation of RAS signaling. Moreover, ARAF amplification causes resistance of lung cancers to EGFR inhibition.
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影响因子：
28.2
作者：
Diamond EL;Durham BH;Haroche J;Yao Z;Ma J;Parikh SA;Wang Z;Choi J;Kim E;Cohen-Aubart F;Lee SC;Gao Y;Micol JB;Campbell P;Walsh MP;Sylvester B;Dolgalev I;Aminova O;Heguy A;Zappile P;Nakitandwe J;Ganzel C;Dalton JD;Ellison DW;Estrada-Veras J;Lacouture M;Gahl WA;Stephens PJ;Miller VA;Ross JS;Ali SM;Briggs SR;Fasan O;Block J;Héritier S;Donadieu J;Solit DB;Hyman DM;Baselga J;Janku F;Taylor BS;Park CY;Amoura Z;Dogan A;Emile JF;Rosen N;Gruber TA;Abdel-Wahab O
通讯作者：
Abdel-Wahab O
影响因子：
28.2
作者：
Fedele C;Ran H;Diskin B;Wei W;Jen J;Geer MJ;Araki K;Ozerdem U;Simeone DM;Miller G;Neel BG;Tang KH
通讯作者：
Tang KH
影响因子：
4.8
作者：
Baljuls, Angela;Mueller, Thomas;Rapp, Ulf R.
通讯作者：
Rapp, Ulf R.
影响因子：
4.8
作者：
Kamioka, Yuji;Yasuda, Shuhei;Matsuda, Michiyuki
通讯作者：
Matsuda, Michiyuki
影响因子：
82.9
作者：
Dardaei L;Wang HQ;Singh M;Fordjour P;Shaw KX;Yoda S;Kerr G;Yu K;Liang J;Cao Y;Chen Y;Lawrence MS;Langenbucher A;Gainor JF;Friboulet L;Dagogo-Jack I;Myers DT;Labrot E;Ruddy D;Parks M;Lee D;DiCecca RH;Moody S;Hao H;Mohseni M;LaMarche M;Williams J;Hoffmaster K;Caponigro G;Shaw AT;Hata AN;Benes CH;Li F;Engelman JA
通讯作者：
Engelman JA