MAP2K1
小结
MAP2K1（也称为MEK1）是致癌基因，编码蛋白是丝氨酸/苏氨酸激酶，是一种细胞内激酶，其在促分裂原活化蛋白激酶（MAPK）信号级联中起效应蛋白的作用。MAPK信号传导途径参与多种细胞过程的调节，包括增殖，分化，细胞粘附和转录。其作为三层MAPK级联的组分，MEK1活性依赖于上游RAF激酶的磷酸化。活化的MEK1依次磷酸化ERK1 / 2（细胞外信号调节的激酶1/2），然后其作为转录调节因子（PMID：22177953）。这些信号传导事件由激活上游受体酪氨酸激酶的生长因子，细胞因子和激素触发，最终导致细胞生长，分化，增殖和存活的关键调节因子的表达改变。MEK1信号传导的失调通常与RAS和RAF中的遗传改变相关。在人类癌症中经常观察到MAPK途径的过度活化，例如黑素瘤，结直肠癌和肺癌；然而，原发性肿瘤中MEK1的致癌突变很少发生。
MAP2K1 (also known as MEK1) is a serine/threonine kinase that functions as an effector protein in the mitogen-activated protein kinase (MAPK) signaling cascade. The MAPK signaling pathway is involved in the regulation of diverse cellular processes including proliferation, differentiation, cell adhesion and transcription. As a component of a three-tiered MAPK cascade, MEK1 activity is dependent on phosphorylation by upstream RAF kinases. Activated MEK1 in turn phosphorylates ERK1/2 (extracellular-signal-regulated kinases1/2) which then serves as a transcriptional regulator . These signaling events are triggered by growth factors, cytokines, and hormones that activate upstream receptor tyrosine kinases, ultimately leading to altered expression of key regulators of cell growth, differentiation, proliferation and survival. Dysregulation of MEK1 signaling is commonly associated with genetic alterations in RAS and RAF. Hyperactivation of the MAPK pathway is frequently observed in human cancers, such as melanoma, colorectal and lung cancers; however, oncogenic mutations in MEK1 in primary tumors are infrequent. The MEK1/2 inhibitors trametinib and cobimetinib are FDA-approved for the treatment of melanoma in combination with RAF inhibition and preclinical and clinical efforts are ongoing to determine the efficacy of MEK1 inhibition for other indications . Some MEK1 mutations may confer resistance to both MEK and RAF inhibitors and can arise as a resistance mechanism to RAF inhibition.