RETINOIDS, M6P/IGF II RECEPTOR & CELL GROWTH REGULATION

类维生素A和甘露糖6-磷酸/胰岛素样生长 已经显示因子-II（M6 P/IGF 2）受体在调节胰岛素抵抗中起基础作用， 在发育和肿瘤发生中控制细胞生长的作用。 最近的研究发现，维甲酸（RA）与M6 P/IGF 2结合， 受体具有高亲和力，导致改变的主要 受体的功能和抑制细胞生长。 这些 研究结果表明，M6 P/IGF 2受体介导了一种新的RA反应， 这可能是重要的细胞生长调节途径。 但 这一途径的分子机制仍然是未知的。 因此，本提案的总体目标是了解RA如何 与M6 P/IGF 2受体相互作用，这种相互作用的作用 在细胞生长调节中。 我们希望解决的关键问题 1）受体蛋白的功能结构域在哪里 负责类维生素A的结合 2)什么是正宗的生物 互动的后果？（3）它们是如何工作的？ 因此，委员会认为， 本申请的具体目的是：（1）鉴定类维生素A M6 P/IGF 2受体结合位点的研究;（2） RA-M6 P/IGF 2 R相互作用的生物学后果。 (3)到 确定生物化学过程负责的生物 RA-M6 P/IGF 2 R相互作用的影响。 我们一般的做法是创造 突变M6 P/IGF 2 R不能结合RA，然后评估 表达野生型RA的细胞之间对RA的功能反应 M6 P/IGF 2 R和具有突变受体的那些。 的主要方法 可使用的方法包括蛋白质诱变、光亲和标记、氨基酸 序列分析，配体结合试验，免疫检测，酶 含量测定和形态学分析。 该项目将提供以下基本信息： 类维生素A如何与M6 P/IGF 2受体相互作用，并揭示了 这种新的类维生素A反应途径在调节细胞凋亡中的作用 增长 这些知识可能会导致新的或更有效的治疗 以及癌症和发育缺陷的预防方法。

Both retinoids and the mannose 6-phosphate/insulin-like growth factor-II (M6P/IGF2) receptor have been shown to play fundamental roles in the control of cell growth in development and oncogenesis. Recent work has discovered that retinoic acid (RA) binds to the M6P/IGF2 receptor with high affinity, leading to alteration of the primary functions of the receptor and suppression of cell growth. These findings suggest that M6P/IGF2 receptor mediates a novel RA response pathway that may be important in cell growth regulation. However, the molecular mechanism underlying this pathway remains largely unknown. Thus, the overall goal of this proposal is to understand how RA interacts with the M6P/IGF2 receptor and the role of this interaction in cell growth regulation. The key questions that we wish to address are: 1) Where is the functional domain of the receptor protein responsible for retinoid binding? 2) What is the authentic biological consequence of the interaction? and 3) How do they work? Accordingly, the specific aims of this application are: (1) To identify the retinoid binding site of the M6P/IGF2 receptor; (2) To extend the understanding of the biological consequence of the RA-M6P/IGF2R interaction. (3) To identify the biochemical processes responsible for the biological effect of RA-M6P/IGF2R interaction. Our general approach is to create a mutant M6P/IGF2R that fails to bind RA and then assess differences of functional responses to RA between the cells expressing wild-type M6P/IGF2R and those with the mutant receptor. The principal methods to be used include protein mutagenesis, photoaffinity labeling, amino acid sequence analysis, ligand binding assay, immuno-detection, enzymatic assay and morphological analysis. Significance This project will provide fundamental information about how retinoids interact with the M6P/IGF2 receptor and shed light on the role of this novel retinoid-response pathway in regulation of cell growth. This knowledge may lead to novel or more effective therapeutic and preventive approaches for cancer and developmental defects.