细胞的正常功能直接关系着器官动态平衡和个体发育，功能异常则导致疾病产生。TGF-beta信号是抑制细胞增殖的主要机制，它的失活则会导致细胞增殖失调。作为TGF-beta信号的关键效应蛋白，SMAD4在消化系统肿瘤中发生突变或缺失，导致了肿瘤细胞增殖不受TGF-beta信号的抑制。在多数其它肿瘤中，SMAD4的遗传变异却不常见，而且这些肿瘤细胞仍然能够逃逸TGF-beta的抑制，但是具体的逃逸机制并不清楚。本实验室首次发现了激酶ALK对SMAD4进行酪氨酸磷酸化，长期以来本领域认为SMAD蛋白主要受丝氨酸/苏氨酸磷酸化的调控。进一步工作表明，酪氨酸磷酸化抑制了SMAD4对TGF-beta靶基因的转录调控，从而阻断了TGF-beta对细胞增殖的抑制。本项目将深入研究SMAD4酪氨酸磷酸化如何调控细胞增殖的分子机制，它将为肿瘤细胞增殖失调提供新的理论依据，以及为临床中肿瘤检测与防治提供新的思路。

Tissue homeostasis and development depends on normal functions of all cell types in the body. Proliferation of normal cells requires the availability of appropriate growth signals. Transforming growth factor-beta (TGF-beta) inhibits the growth of most epithelial and hematopoietic cells, and thus controls a wide variety of developmental processes, including cell and tissue differentiation, morphogenetic processes and embryonic organization. The early physiologic changes during tumor development include sustained activation of mitogenic signals and the loss of sensitivity to TGF-beta. As a result, tumor cells proliferate in an uncontrolled fashion and are often resistant to the antiproliferative response to TGF-beta. In line with this, inactivating mutations and deletions of the central TGF-beta signal transducer Smad4 are common in gastrointestinal and pancreatic cancers, leading to loss of TGF-beta responses. Yet, genetic alterations in the TGF-beta pathways are rare in certain cancers such as lymphoma, lung cancer and neuroblastoma. This suggests an existence of alternative mechanisms underlying TGF-beta resistance. Thus, our long-term goal is to understand the molecular basis of how antiproliferative growth factors such as TGF-beta regulate cell growth and differentiation, and the underlying mechanisms through which alterations in antiproliferative signaling pathways lead to deregulation of growth control in human diseases. Our short-term strategy is to elucidate the mechanism underlying how Smad4 tyrosine phosphorylation affects TGF-beta growth suppressing functions. In preliminary studies, we have for the first time found that Smad4 binds to protein tyrosine kinase ALK and becomes phosphorylated by ALK. Herein we propose to determine a physiological function of Smad4 tyrosine phosphorylation in inhibiting TGF-beta antiproliferative actions and in promoting tumorigenesis. Our proposed studies will not only provide further understanding of the molecular basis underlying TGF-beta signaling in the normal tissues, gain novel insights into the mechanism of TGF-beta resistance in cancer, but also have strong clinical implications in developing new diagnostic tools and therapies for the prevention and treatment of human diseases.