据一篇发表于Nature杂志的研究报告称，蒙特利尔大学的研究人员Marc Therrien等人发现了RAF蛋白激酶的激活机制，而超过25%的癌症都与RAF蛋白激酶突变有关，了解该机制对开发全新的抗癌药物，降低化疗引起的毒副作用具有重要的意义。
RAF激酶家族能调节细胞生长、分化以及生存等一系列生命过程。Therrien及其同事Sicheri首次证实，两个RAF蛋白发生二聚化对激活该蛋白至关重要。如果抑制RAF二聚化则会阻断激活过程，从而终止癌细胞的生长。
该研究不仅发现了RAF的激活机制，还揭示了控制其他蛋白激酶的潜在机制——许多激酶都与癌症或其他疾病(如糖尿病，高血压，神经退行性疾病等)的发病有关。（生物谷Bioon.com）
生物谷推荐原始出处：
Nature advance online publication 2 September 2009 | doi:10.1038/nature08314
A dimerization-dependent mechanism drives RAF catalytic activation
Thanashan Rajakulendran1,2,5, Malha Sahmi3,5, Martin Lefran?ois3, Frank Sicheri1,2 & Marc Therrien3,4
1 Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada
2 Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada
3 Institute for Research in Immunology and Cancer, Laboratory of Intracellular Signaling,
4 Département de pathologie et de biologie cellulaire, Université de Montréal, Montréal, Québec H3C 3J7, Canada
5 These authors contributed equally to this work.
The ERK (extracellular signal-regulated kinase) pathway is an evolutionarily conserved signal transduction module that controls cellular growth, differentiation and survival1. Activation of receptor tyrosine kinases (RTKs) by the binding of growth factors initiates GTP loading of RAS, which triggers the initial steps in the activation of the ERK pathway by modulating RAF family kinase function. Once activated, RAF participates in a sequential cascade of phosphorylation events that activate MEK, and in turn ERK. Unbridled signalling through the ERK pathway caused by activating mutations in RTKs, RAS or RAF has been linked to several human cancers2. Of note, one member of the RAF family, BRAF, is the most frequently mutated oncogene in the kinase superfamily3. Not surprisingly, there has been a colossal effort to understand the underlying regulation of this family of kinases. In particular, the process by which the RAF kinase domain becomes activated towards its substrate MEK remains of topical interest. Here, using Drosophila Schneider S2 cells, we demonstrate that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which we term the side-to-side dimer. Moreover, we find that the RAF-related pseudo-kinase KSR (kinase suppressor of Ras) also participates in forming side-to-side heterodimers with RAF and can thereby trigger RAF activation. This mechanism provides an elegant explanation for the longstanding conundrum about RAF catalytic activation, and also provides an explanation for the capacity of KSR, despite lacking catalytic function, to directly mediate RAF activation. We also show that RAF side-to-side dimer formation is essential for aberrant signalling by oncogenic BRAF mutants, and identify an oncogenic mutation that acts specifically by promoting side-to-side dimerization. Together, our data identify the side-to-side dimer interface of RAF as a potential therapeutic target for intervention in BRAF-dependent tumorigenesis.
