SOCS-3 in IGF-IR Signaling in Malignant Cells

SOCS-3 在恶性肿瘤细胞中 IGF-IR 信号转导中的作用

• 批准号: 6548154
• 负责人: BHAKTA R DEY
• 金额: $ 7.13万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-23 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6548154
• 关键词: SDS polyacrylamide gel electrophoresis; apoptosis; autoradiography; biological signal transduction; cell growth regulation; cell line; cell proliferation; cytokine; enzyme activity; growth factor receptors; immunoprecipitation; insulinlike growth factor; mitogen activated protein kinase; neoplastic cell; neoplastic growth; phosphatidylinositol 3 kinase; phosphorylation; protein kinase; protein structure function; transcription factor; western blottings

DESCRIPTION (provided by applicant) The insulin-like growth factor-I receptor (IGF-IR) plays an important role in promoting the growth of cancers by stimulating malignant cell proliferation and transformation, and inhibiting apoptosis. We identified suppressor of cytokine signaling (SOCS)-3 as an intracellular binding partner of the IGF-IR. In human colon cancer Caco-2 cells, the IGF-IR and IGF-II are expressed at high levels and SOCS-3 is significantly induced by IGF-I stimulation. SOCS-3 protein is heavily phosphorylated in serine residues and this serine phosphorylation is noticed with or without IGF-I stimulation. SOCS-3 protein localized mostly in the cytoplasm and IGF-I stimulation results in both nuclear and cytoplasmic localization. Moreover, SOCS-3 protein is ubiquitinated in mammalian cells. These results suggest that SOCS-3 protein may play regulatory roles in IGF-IR signaling. SOCS-3 has been shown to be a negative regulator of interleukin (IL-2, IL-6), growth hormone, prolactin, insulin and leptin receptor signaling pathways. The primary goal of this study is to define the function of SOCS-3 in IGF-IR signaling in malignant cells. We hypothesize that SOCS-3 may play a negative regulatory role in IGF-IR signaling in malignant cells. To test this hypothesis we formulated the following specific aims: 1) to identify which signal transduction pathway(s) of the IGF-IR might be affected by the IGF-IR-SOCS-3 interaction, 2) to determine whether this interaction alters kinase activity or stability of the receptor, and 3) to determine the mechanisms by which IGF-IR-SOCS-3 interaction might interfere with IGF-I stimulated proliferation, invasion and inhibition of apoptosis in malignant cells. Our long-term goal is to investigate the negative regulation of the IGF-IR signaling by SOCS-3, a potentially novel mechanism for growth resistance and cancer prevention.

描述（由申请人提供）胰岛素样生长因子-I受体（IGF-IR）通过刺激恶性细胞增殖和转化并抑制细胞凋亡而在促进癌症的生长中起重要作用。我们将细胞因子信号传导（SOCS）-3的抑制剂确定为IGF-IR的细胞内结合伴侣。在人类结肠癌CACO-2细胞中，IGF-IR和IGF-II高水平表达，SOCS-3由IGF-I刺激显着诱导。 SOCS-3蛋白在丝氨酸残基中大量磷酸化，并且在有或没有IGF-I刺激的情况下，这种丝氨酸磷酸化被注意到。 SOCS-3蛋白主要在细胞质和IGF-I刺激中局部定位，从而导致核和细胞质定位。此外，SOCS-3蛋白在哺乳动物细胞中泛素化。这些结果表明，SOCS-3蛋白可能在IGF-IR信号传导中起调节作用。 SOCS-3已被证明是白介素（IL-2，IL-6），生长激素，催乳素，胰岛素和瘦素受体信号通路的负调节剂。这项研究的主要目标是定义SOCS-3在恶性细胞中IGF-IR信号传导中的功能。我们假设SOCS-3可能在恶性细胞中的IGF-IR信号传导中起负调控作用。为了检验该假设，我们制定了以下特定目的：1）确定IGF-IR的信号转导途径可能会受到IGF-IR-SOCS-3相互作用的影响，2）以确定受体的激酶活性或稳定性是否会逐步确定IGF-IG-3相互作用的机制，以确定这种相互作用的活性或稳定性。和抑制恶性细胞凋亡。我们的长期目标是研究SOCS-3对IGF-IR信号传导的负调控，这是一种潜在的新型耐药性和预防癌症的机制。