Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling.
Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling.
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DOI：
10.1016/j.molcel.2012.12.018
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发表时间：
2013-02-21
期刊：
影响因子：
16
通讯作者：
Morrison, Deborah K.
中科院分区：
文献类型：
--
作者：
Freeman, Alyson K.;Ritt, Daniel A.;Morrison, Deborah K.
Raf激酶对于正常的Ras-Raf-MEK-ERK通路信号传导是必需的，并且该通路的组分中的激活突变与多种人类癌症以及相关的发育障碍努南、LEOPARD和心面皮肤综合征相关。尽管已知Raf激酶在正常和疾病相关的Raf信号传导期间二聚化，但Raf二聚化的功能意义尚未完全阐明。在这里，使用突变分析和肽抑制剂，我们表明，二聚化是需要正常的Ras依赖性Raf激活和疾病相关的Raf突变体的生物学功能与中度，低，或受损的激酶活性。然而，具有高催化活性的B-Raf突变体（如V600 E-B-Raf）的功能不需要二聚化。重要的是，我们发现，二聚体界面肽可以有效地阻止Raf二聚化和抑制Raf信号时，Raf功能所需的二聚化，从而确定Raf二聚体接口作为治疗靶点。
Raf kinases are essential for normal Ras-Raf-MEK-ERK pathway signaling, and activating mutations in components of this pathway are associated with a variety of human cancers, as well as the related developmental disorders Noonan, LEOPARD, and cardiofaciocutaneous syndromes. Although the Raf kinases are known to dimerize during normal and disease-associated Raf signaling, the functional significance of Raf dimerization has not been fully elucidated. Here, using mutational analysis and a peptide inhibitor, we show that dimerization is required for normal Ras-dependent Raf activation and for the biological function of disease-associated Raf mutants with moderate, low, or impaired kinase activity. However, dimerization is not needed for the function of B-Raf mutants with high catalytic activity, such as V600E-B-Raf. Importantly, we find that a dimer interface peptide can effectively block Raf dimerization and inhibit Raf signaling when dimerization is required for Raf function, thus identifying the Raf dimer interface as a therapeutic target.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
DOI：
10.1002/ajmg.c.30295
发表时间：
2011-05-15
影响因子：
3.1
作者：
Allanson, Judith E.;Anneren, Goran;Zenker, Martin
通讯作者：
Zenker, Martin
DOI：
10.1016/j.beem.2010.09.002
发表时间：
2011-02
期刊：
Best practice & research. Clinical endocrinology & metabolism
影响因子：
--
作者：
Tartaglia M;Gelb BD;Zenker M
通讯作者：
Zenker M
DOI：
10.1056/nejmoa1002011
发表时间：
2010-08-26
期刊：
The New England journal of medicine
影响因子：
--
作者：
Flaherty KT;Puzanov I;Kim KB;Ribas A;McArthur GA;Sosman JA;O'Dwyer PJ;Lee RJ;Grippo JF;Nolop K;Chapman PB
通讯作者：
Chapman PB
影响因子：
16
作者：
Garnett, MJ;Rana, S;Marais, R
通讯作者：
Marais, R