TGF Beta Receptor Dynamics

转化生长因子β （TGF-ß）生物学的一个中心悖论是，相同的生长因子如何诱导生长刺激（即间充质细胞）和生长抑制（即上皮细胞）等不同的反应？考虑到TGF-ß在许多正常和病理条件中的关键作用，如果我们希望制定具体的干预策略，解决这个问题是至关重要的。为此，我们一直在研究一般假设，即细胞对TGF-ß的反应依赖于运输和信号机制的综合作用。为了支持这一建议，我们已经确定(i)在极化上皮细胞中TGF-ß受体运输到基底外侧结构域，靠近连接复合体；（ii）哺乳动物逆转录复合物通过网格蛋白、EEA1和Rab11阳性区室控制内小体向质膜的再循环，从而特异性地维持ii型TGF-ß受体的极性；（iii）分类连接蛋白9 （SNX9）是一种已知的转运蛋白，在TGF-ß典型质膜作用下游的信号传导中有新的作用；（iv）已经确定了一种独特的机制，通过这种机制可以控制TGF-ß信号的特异性，并随后利用它来治疗依赖于Smad3的疾病；(v)促纤维化TGF-ß反应需要PDGF和ErbB受体酪氨酸激酶的协同作用；最重要的是，（vi）利用肺纤维化治疗模型，提供了临床前数据，证明通过靶向TGF-ß调节的多种途径可以稳定肺功能的生理参数。我们建议使用各种生化、生物学和遗传学方法来扩展这些发现。首先，定义控制TGF-ß受体转运的受体元件和细胞因子，以及逆转录物在TGF-ß刺激的EMT/迁移中的作用。

A central paradox in transforming growth factor beta (TGF-ß) biology is how the same growth factor can induce such divergent responses as growth stimulation (i.e., mesenchymal cells) and growth inhibition (i.e., epithelial cells)? Considering the pivotal role TGF-ß has in a number of normal and pathological conditions, addressing that issue is fundamental if we hope to develop specific intervention strategies. To that end, we have been investigating the general hypothesis that the cellular response to TGF-ß is dependent upon an integrated action of the trafficking and signaling machinery. In support of that proposal, we have determined that (i) in polarized epithelial cells TGF-ß receptors traffic to the basolateral domain, adjacent to the junctional complex; (ii) the mammalian retromer complex specifically maintains type II TGF-ß receptor polarity by controlling recycling endosome to plasma membrane delivery by way of clathrin, EEA1 and Rab11 positive compartments; (iii) sorting nexin 9 (SNX9), a known trafficking protein, has a new role in TGF-ß signaling downstream of its canonical plasma membrane action; (iv) an unique mechanism has been defined by which specificity in TGF-ß signaling can be controlled and subsequently exploited to treat diseases dependent upon Smad3; (v) profibrotic TGF-ß responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases; and, most importantly, (vi) utilizing a treatment model of lung fibrosis, provided preclinical data documenting that physiologic parameters of lung function can be stabilized by targeting multiple TGF-ß regulated pathways. We propose to extend these findings using a variety of biochemical, biological, and genetic approaches. First, the receptor elements and cellular factors controlling TGF-ß receptor trafficking as well as the role of retromer in TGF-ß stimulated EMT/migration will be defined. As a number of diseases result from defects in the ability to sort or transport proteins to defined cellular locales, characterizing the operative trans-acting factors provides potential mechanisms to alter the cellular response to TGF-ß. Second, the role of SNX9 in regulating Smad3-dependent phenotypes including lung fibrosis and glioblastoma progression will be determined. In that upwards of 45% of all deaths in the developed world are attributed to some sort of chronic fibroproliferative disorder, and the median progression-free and survival for glioblastoma with current chemoradiation is ~7 and 15 months, respectively, new approaches are clearly needed.