Mu Dezhi, Cambier Stephanie, Fjellbirkeland Lars, Baron Jody L, Munger John S, Kawakatsu Hisaaki, Sheppard Dean, Broaddus V Courtney, Nishimura Stephen L
Department of Pathology, University of California at San Francisco/Mt. Zion Cancer Center, San Francisco, CA 94143, USA.
J Cell Biol. 2002 Apr 29;157(3):493-507. doi: 10.1083/jcb.200109100. Epub 2002 Apr 22.
Integrins, matrix metalloproteases (MMPs), and the cytokine TGF-beta have each been implicated in homeostatic cell behaviors such as cell growth and matrix remodeling. TGF-beta exists mainly in a latent state, and a major point of homeostatic control is the activation of TGF-beta. Because the latent domain of TGF-beta1 possesses an integrin binding motif (RGD), integrins have the potential to sequester latent TGF-beta (SLC) to the cell surface where TGF-beta activation could be locally controlled. Here, we show that SLC binds to alpha(v)beta8, an integrin expressed by normal epithelial and neuronal cells in vivo. This binding results in the membrane type 1 (MT1)-MMP-dependent release of active TGF-beta, which leads to autocrine and paracrine effects on cell growth and matrix production. These data elucidate a novel mechanism of cellular homeostasis achieved through the coordination of the activities of members of three major gene families involved in cell-matrix interactions.
整合素、基质金属蛋白酶（MMPs）和细胞因子转化生长因子-β（TGF-β）均与细胞生长和基质重塑等稳态细胞行为有关。TGF-β主要以潜伏状态存在，稳态控制的一个关键点是TGF-β的激活。由于TGF-β1的潜伏结构域具有整合素结合基序（RGD），整合素有可能将潜伏性TGF-β（SLC）隔离到细胞表面，在那里TGF-β的激活可以受到局部控制。在这里，我们表明SLC与α（v）β8结合，α（v）β8是一种在体内正常上皮细胞和神经元细胞中表达的整合素。这种结合导致活性TGF-β以膜型1（MT1）-MMP依赖的方式释放，从而对细胞生长和基质产生自分泌和旁分泌作用。这些数据阐明了一种通过协调参与细胞-基质相互作用的三个主要基因家族成员的活性来实现细胞稳态的新机制。
