BakerIDI Heart and Diabetes Institute, Commercial Road, Melbourne, Victoria 3004, Australia.
Int J Biochem Cell Biol. 2012 May;44(5):722-7. doi: 10.1016/j.biocel.2012.01.018. Epub 2012 Feb 2.
The current paradigm of G protein coupled receptor signaling involves a classical pathway being the activation of phospholipase C and the generation of 1,4,5-inositol trisphosphate, signaling through β-arrestin scaffold molecules and the transactivation of tyrosine kinase growth factor receptors. Transactivation greatly expands the range of signaling pathways and responses attributable to the receptor. Recently it has been revealed that G protein coupled receptor agonists can also transactivate the serine/threonine kinase cell surface receptor for transforming growth factor-β (Alk5). This leads to the generation of carboxyl terminal phosphorylated Smad2 which is the immediate downstream product of the activated Alk5. Thus, the current paradigm of G protein coupled signaling can be expanded to include the transactivation of the serine kinase receptor Alk5. These insights expand the possibilities for outcomes of therapeutically targeting GPCRs where more substantive and prolonged actions such as the synthesis of extracellular matrix may be affected.
目前 G 蛋白偶联受体信号转导的模式涉及经典途径，即激活磷脂酶 C 并生成 1,4,5-肌醇三磷酸，通过β-arrestin 支架分子进行信号转导，并激活酪氨酸激酶生长因子受体。转激活大大扩展了受体归因于的信号通路和反应的范围。最近发现，G 蛋白偶联受体激动剂也可以转激活转化生长因子-β（Alk5）的细胞表面丝氨酸/苏氨酸激酶受体。这导致羧基末端磷酸化 Smad2 的产生，Smad2 是激活的 Alk5 的直接下游产物。因此，G 蛋白偶联信号转导的当前模式可以扩展到包括丝氨酸激酶受体 Alk5 的转激活。这些新发现扩展了治疗性靶向 GPCR 的可能性，其中可能会受到更实质性和更持久的作用，例如细胞外基质的合成。
