Molecular and Cellular Biology of Thrombopoietin

血小板生成素(TPO)是血小板生成的主要调节因子。通过ITS 与c-MPL受体相互作用，TPO通过触发 JAK2的磷酸化和激活。尽管这一点已经确立，但它仍然 不清楚TPO信号是如何调制的，这对 细胞生长和分化的调节。TPO信号转导失调，AS 以赋予JAK2或c-MPL结构性活性的突变为例，已知 先天性和获得性骨髓增生性疾病的发生 (MPDS)，包括真性红细胞增多症(PV)、原发性血小板增多症(ET)和 特发性骨髓纤维化(IMF)。此外，TPO模拟正在成为重要的 良性和肿瘤性血小板减少症患者的治疗工具 病因学。在这次竞争更新中，我们建议研究TPO的监管 信号转导包括：1)c-MPL受体对TPO的转运和内化； 2)TPO信号的负调控，包括受体的潜在作用 泛素化、Src家族激酶、磷酸酶和张力蛋白同源(PTEN) 巨核细胞生成；3)TPO和TPO的功能异同 促红细胞生成素(EPO)信号。

Thrombopoietin (TPO) is the primary regulator of thrombopoiesis. Through its interaction with the c-Mpl receptor, TPO initiates a signaling cascade by triggering the phosphorylation and activation of Jak2. Although this is well established, it remains unclear as to how TPO signaling is modulated, which has important consequences for the regulation of cell growth and differentiation. Dysregulation of TPO signaling, as exemplified by mutations conferring constitutive activity to Jak2 or c-Mpl, is known to underlie the development of congenital and acquired myeloproliferative disorders (MPDs), including polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF). In addition, TPO-mimetics are emerging as important tools for the treatment of patients with thrombocytopenia of both benign and neoplastic etiologies. In this competitive renewal we propose to study the regulation of TPO signaling, including: 1) c-Mpl receptor trafficking and internalization in response to TPO, 2) negative regulation of TPO signaling, including the potential effects of receptor ubiquitination, Src family kinases and phosphatase and tensin homologue (PTEN) for megakaryopoiesis, and 3) functional similarities and differences between TPO and erythropoietin (EPO) signaling.