Jenkins Gisli
University of Nottingham, Clinical Sciences Building, Nottingham City Hospital, Nottingham NG5 1PB, UK.
Int J Biochem Cell Biol. 2008;40(6-7):1068-78. doi: 10.1016/j.biocel.2007.11.026. Epub 2007 Dec 15.
Transforming growth factor-beta (TGFbeta) plays a central role in a number of developmental and pathological processes. There are 3 isoforms of TGFbeta (1-3) and all are sequestered in the extracellular matrix as latent complexes. Activation of this complex is the key biological checkpoint controlling TGF-beta bioavailability. This process is tightly regulated in a temporal, spatial and isoform specific manner highlighting its importance. There are many different mechanisms by which TGF-beta can be activated. Both serine and metalloproteinases play an important role in TGF-beta activation, at least in vitro, and many of these proteases have been implicated in pathological conditions. The mechanism of activation is distinct between the different proteases, but is not conserved between the two groups. Both serine proteases, such as plasmin, and metalloproteases, such as MMP2, can directly cleave latent TGFbeta, whereas others, such as thrombin and MMP14, interact with integrin mediated TGFbeta activation pathways. However, further studies are still required to fully understand the relevance of all of these pathways in vivo. Currently, the best described mechanism of TGF-beta1 activation in vivo is by integrins, although this process can be modulated by proteases. The primary mechanism of TGF-beta2 and TGF-beta3 activation has yet to be defined in vivo, although it is likely that TGF-beta3 is activated in a similar manner to TGF-beta1. This review describes the mechanism of protease driven TGF-beta activation, and discusses the physiological and pathological relevance of this process.
转化生长因子-β（TGFβ）在许多发育和病理过程中发挥着核心作用。TGFβ有3种亚型（1 - 3），它们均以潜伏复合物的形式隔离于细胞外基质中。该复合物的激活是控制TGF-β生物利用度的关键生物学检查点。这一过程在时间、空间和亚型特异性方面受到严格调控，凸显了其重要性。TGF-β的激活有许多不同机制。丝氨酸蛋白酶和金属蛋白酶在TGF-β激活中均发挥重要作用，至少在体外是如此，而且其中许多蛋白酶与病理状况有关。不同蛋白酶的激活机制各不相同，且两组之间并不保守。丝氨酸蛋白酶（如纤溶酶）和金属蛋白酶（如MMP2）均可直接切割潜伏性TGFβ，而其他一些蛋白酶（如凝血酶和MMP14）则与整合素介导的TGFβ激活途径相互作用。然而，仍需要进一步研究以充分了解所有这些途径在体内的相关性。目前，体内TGF-β1激活的最佳描述机制是通过整合素，尽管这一过程可受蛋白酶调节。TGF-β2和TGF-β3激活的主要机制在体内尚未明确，不过TGF-β3可能以与TGF-β1类似的方式被激活。本综述描述了蛋白酶驱动的TGF-β激活机制，并讨论了这一过程的生理和病理相关性。
