Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.
Crit Rev Biochem Mol Biol. 2013 Jul-Aug;48(4):332-56. doi: 10.3109/10409238.2013.790873. Epub 2013 May 3.
Protein kinases represent one of the largest families of genes found in eukaryotes. Kinases mediate distinct cellular processes ranging from proliferation, differentiation, survival, and apoptosis. Ligand-mediated activation of receptor kinases can lead to the production of endogenous hydrogen peroxide (H₂O₂) by membrane-bound NADPH oxidases. In turn, H₂O₂ can be utilized as a secondary messenger in signal transduction pathways. This review presents an overview of the molecular mechanisms involved in redox regulation of protein kinases and its effects on signaling cascades. In the first half, we will focus primarily on receptor tyrosine kinases (RTKs), whereas the latter will concentrate on downstream non-receptor kinases involved in relaying stimulant response. Select examples from the literature are used to highlight the functional role of H₂O₂ regarding kinase activity, as well as the components involved in H₂O₂ production and regulation during cellular signaling. In addition, studies demonstrating direct modulation of protein kinases by H₂O₂ through cysteine oxidation will be emphasized. Identification of these redox-sensitive residues may help uncover signaling mechanisms conserved within kinase subfamilies. In some cases, these residues can even be exploited as targets for the development of new therapeutics. Continued efforts in this field will further basic understanding of kinase redox regulation, and delineate the mechanisms involved in physiological and pathological H₂O₂ responses.
蛋白激酶是真核生物中最大的基因家族之一。激酶介导了从增殖、分化、存活到凋亡等不同的细胞过程。配体介导的受体激酶激活可导致膜结合 NADPH 氧化酶产生内源性过氧化氢 (H₂O₂)。反过来，H₂O₂可以作为信号转导途径中的第二信使。本文综述了蛋白激酶氧化还原调控及其对信号级联的影响的分子机制。在前半部分，我们将主要关注受体酪氨酸激酶 (RTKs)，而后半部分将集中讨论参与传递刺激反应的下游非受体激酶。文献中的一些实例被用来突出 H₂O₂对激酶活性的功能作用，以及在细胞信号转导过程中 H₂O₂产生和调节所涉及的成分。此外，还强调了 H₂O₂通过半胱氨酸氧化直接调节蛋白激酶的研究。鉴定这些氧化还原敏感残基可以帮助揭示激酶亚家族中保守的信号机制。在某些情况下，这些残基甚至可以被用作开发新疗法的靶点。该领域的持续努力将进一步加深对激酶氧化还原调控的基础理解，并阐明生理和病理 H₂O₂反应所涉及的机制。
