Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742, USA.
Biochem Biophys Res Commun. 2010 Aug 27;399(3):313-7. doi: 10.1016/j.bbrc.2010.07.092. Epub 2010 Jul 30.
A-RAF, B-RAF, and C-RAF are a family of three protein-serine/threonine kinases that participate in the RAS-RAF-MEK-ERK signal transduction cascade. This cascade participates in the regulation of a large variety of processes including apoptosis, cell cycle progression, differentiation, proliferation, and transformation to the cancerous state. RAS mutations occur in 15-30% of all human cancers, and B-RAF mutations occur in 30-60% of melanomas, 30-50% of thyroid cancers, and 5-20% of colorectal cancers. Activation of the RAF kinases requires their interaction with RAS-GTP along with dephosphorylation and also phosphorylation by SRC family protein-tyrosine kinases and other protein-serine/threonine kinases. The formation of unique side-to-side RAF dimers is required for full kinase activity. RAF kinase inhibitors are effective in blocking MEK1/2 and ERK1/2 activation in cells containing the oncogenic B-RAF Val600Glu activating mutation. RAF kinase inhibitors lead to the paradoxical increase in RAF kinase activity in cells containing wild-type B-RAF and wild-type or activated mutant RAS. C-RAF plays a key role in this paradoxical increase in downstream MEK-ERK activation.
A-RAF、B-RAF 和 C-RAF 是一组三种蛋白丝氨酸/苏氨酸激酶，参与 RAS-RAF-MEK-ERK 信号转导级联反应。该级联反应参与调节多种过程，包括细胞凋亡、细胞周期进程、分化、增殖和癌变。RAS 突变发生在所有人类癌症的 15-30%中，B-RAF 突变发生在 30-60%的黑色素瘤、30-50%的甲状腺癌和 5-20%的结直肠癌中。RAF 激酶的激活需要其与 RAS-GTP 相互作用，同时还需要 SRC 家族蛋白酪氨酸激酶和其他蛋白丝氨酸/苏氨酸激酶的去磷酸化和磷酸化。独特的侧向 RAF 二聚体的形成对于充分的激酶活性是必需的。RAF 激酶抑制剂可有效阻断含有致癌性 B-RAF Val600Glu 激活突变的细胞中 MEK1/2 和 ERK1/2 的激活。RAF 激酶抑制剂导致含有野生型 B-RAF 和野生型或激活突变型 RAS 的细胞中 RAF 激酶活性的反常增加。C-RAF 在这种下游 MEK-ERK 激活的反常增加中起着关键作用。
