ErbB Signaling in Liver Ontogeny and Regeneration

我们的长期目标是了解控制生长的机制， 分化和肝脏再生。表皮生长因子（EGF）及其 同源物是在控制肝脏生长中研究最彻底的生长因子， 再生和致癌作用。EGF与肝脏的关系 复杂，因为我们现在知道有多种EGF样分子， 通过四种不同的受体ErbB蛋白起作用。ErbB酪氨酸信号 激酶不仅取决于存在哪种配体，还取决于存在哪种配体的组合。 受体被募集到信号复合物中。也有负调节器， ErbB信号传导，如酪氨酸磷酸酶和蛋白质，如Ralt，复合物 直接与ErbB蛋白结合这种分析也因其他因素的作用而复杂化。 与ErbB蛋白相互作用的受体，包括c-met，HGF的受体。我们 其他研究表明，c-met需要一个功能性EGF受体才能发挥作用。 对运动和有丝分裂的影响这项资助的重点是ErbB受体所起的作用， 作为肝脏生长和分化的调节剂。我们创造了肝细胞特异性 EGFr、ErbB 2和ErbB 3缺陷小鼠，并获得了 肝脏特异性cMet基因缺失小鼠。这项建议的具体目标是：1） 确定ErbB蛋白和c-met在有丝分裂信号传导中的相互作用， 正常和再生肝脏; 2）评估ErbB蛋白作为 HGF的信号转导。朝着这些目标取得进展将增进我们对 EGF样分子如何在正常组织中发出信号，肝脏如何分化成 成年人的功能形式，以及这些有效的有丝分裂原如何调节戏剧性的恢复， 再生过程中的肝脏质量。肝再生是一个范例，为其他条件， 正常或改变的生长调节，包括组织肥大、伤口愈合，以及 癌除了阐明肝脏中生长控制的机制外，我们的 研究可能最终有助于从未分化肝细胞产生成熟肝细胞 用于移植和人工肝的产生。

Our long-term goal is to understand the mechanisms that control the growth, differentiation, and regeneration of the liver. Epidermal growth factor (EGF) and its homologs are the most thoroughly studied growth factors in the control of liver growth, regeneration and carcinogenesis. However, the relationship of EGF to the liver is complex, since we now know that there are multiple EGF-like molecules and that they act through four different receptors, the ErbB proteins. Signaling by ErbB tyrosine kinases depends on not only which ligands are present, but also which combinations of receptors are recruited into signaling complexes. There are also negative regulators of ErbB signaling, such as tyrosine phosphatases and proteins, such as Ralt, that complex directly with the ErbB proteins. This analysis is also complicated by the role of other receptors that interact with the ErbB proteins, including c-met, the receptor for HGF. We and others have shown that c-met requires a functional EGF receptor to elicit its effects on motility and mitogenesis. This grant focuses on the role played by the ErbB receptors as regulators of growth and differentiation in the liver. We have created hepatocytespecific EGFr, ErbB2, and ErbB3 deficient mice by gene targeting, and have obtained liver-specific cMet gene deleted mice. The specific aims of this proposal are to: 1) To define the interactions among the ErbB proteins and c-met in the mitogenic signaling of the normal and regenerating liver; 2) To evaluate the central role of the ErbB proteins as signal tansducers of HGF. Progress toward these aims will improve our understanding of how EGF-like molecules signal in a normal tissue, how the liver differentiates into its adult functional form, and how these potent mitogens regulate the dramatic restoration of liver mass during regeneration. Liver regeneration is a paradigm for other conditions of normal or altered growth regulation, including tissue hypertrophy, wound healing, and cancer. In addition to elucidating the mechanisms of growth control in the liver, our studies may ultimately aid in the generation of mature hepatocytes from undifferentiated cells for transplantation and for the generation of artificial livers.