ErbB Signaling in Liver Ontogeny and Regeneration

我们的长期目标是了解控制增长的机制， 肝脏的分化和再生。表皮生长因子(EGF)及其受体 同系物是在控制肝脏生长方面研究最深入的生长因子， 再生和致癌。然而，EGF与肝脏的关系是 复杂，因为我们现在知道有多个类似EGF的分子，它们 通过四种不同的受体发挥作用，ErbB蛋白。ErbB酪氨酸信号转导途径 激酶不仅取决于存在哪些配体，还取决于哪些配体的组合 受体被招募到信号复合体中。也有负面的监管机构 ErbB信号，如酪氨酸磷酸酶和蛋白质，如Ralt，即复合体 直接与ErbB蛋白结合。这一分析也因其他因素的作用而变得复杂 与ErbB蛋白相互作用的受体，包括HGF的受体c-met。我们 还有一些研究表明，c-met需要一个有功能的EGF受体才能发挥作用。 关于运动性和有丝分裂。这项拨款的重点是ErbB受体所扮演的角色 作为肝脏生长和分化的调节器。我们已经创造了肝细胞特异体 通过基因打靶获得了EGFR、ErbB2和ErbB3缺陷小鼠，并获得了 肝脏特异性cMET基因缺失小鼠。这项建议的具体目的是：1) 明确ErbB蛋白和c-met在促有丝分裂信号转导中的相互作用 2)评估ErbB蛋白的中枢作用，如 肝细胞生长因子的信号转导因子。实现这些目标的进展将提高我们的理解 EGF样分子如何在正常组织中发出信号，肝脏如何分化为 成体功能形式，以及这些有效的有丝分裂原如何调节 再生过程中的肝脏肿块。肝脏再生是其他条件下的一个范例 正常或改变的生长调节，包括组织肥大、伤口愈合和 癌症。除了阐明肝脏生长控制的机制外，我们的 研究可能最终有助于从未分化的肝细胞产生成熟的肝细胞 用于移植和人工肝生成的细胞。

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.