TGF-beta receptor sumoylation and cell behavior

自分泌TGF-β信号传导在癌症进展中起关键作用，从而作为肿瘤 抑制剂在早期癌发生中，并在刺激侵袭导致转移中。大多数癌 对TGF-β的反应失调，导致对TGF-β的抗增殖反应失活。 β的在某些情况下，这种失调与I型或II型TGF-β的突变有关。 受体。SUMO化，即泛素样SUMO蛋白的共价连接，是一种新兴的 各种蛋白质的翻译后修饰。类小泛素化的作用通常是不可预测的， 依赖于靶蛋白。SUMO相互作用蛋白的可能募集可能导致 蛋白质复合物的形成和靶蛋白的功能特性。SUMO化主要是 其特征在于涉及核功能的转录因子和蛋白质的修饰，和 细胞表面受体的类小泛素化尚未报道。我们最近发现I型转化生长因子- β受体TbRI是类小泛素化的，这使我们假设类小泛素化调节这种功能。 受体，并因此TGF-β信号传导和细胞对TGF-β的反应。在确定了 在TbRI的类小泛素化位点，我们还发现了一个点突变，在TbRI，这已被发现在协会 与转移性乳腺癌，赋予缺乏sumoylation TbRI。这就引出了一个假设， TbRI的类小泛素化影响自分泌TGF-β信号，是侵袭行为的决定因素 癌细胞 我们提出了三个目标，以确定TbRI类小泛素化的分子机制及其在肿瘤发生中的作用。 细胞对TGF-β的反应和癌细胞在体内的行为。目标1将描述该机制 的SUMO化的TbRI，包括搜索，以确定负责E3 SUMO连接酶。目标2将检查 TbRI类小泛素化对Smad和非Smad信号转导应答以及细胞增殖的影响， 对TGF-β的侵袭反应。这一目标还应定义“转移”和“转移”之间的功能差异。 相关的”TbRI突变体、野生型TbRI和类小泛素化缺陷型TbRI点突变体在信号传导和 细胞行为对TGF-β的反应。最后，目标3将定义TbRI类小泛素化和TbRI类小泛素化的作用。 “转移相关”TbRI点突变对癌细胞行为和癌症进展的影响 vivo.这些研究为进一步阐明TGF-β 1在肿瘤细胞中的作用机制提供了基础。 β受体类小泛素化，其在细胞对TGF-β的反应中的作用以及在癌细胞行为和癌症中的作用 进展

Autocrine TGF-beta signaling plays key roles in cancer progression, thereby acting as tumor suppressor in early carcinogenesis, and in stimulating invasion leading to metastasis. Most carcinomas have a deregulated response to TGF-beta, leading to inactivation of the antiproliferative response to TGF- beta. In some cases this deregulation is associated with mutations in the type I or type II TGF-beta receptors. Sumoylation, i.e. the covalent attachment of a ubiquitin-like SUMO protein, is an emerging posttranslational modification of various proteins. The role of sumoylation is often unpredictable and seems to depend on the target protein. Possible recruitment of SUMO-interacting proteins may lead to changes in the protein complex formation and functional properties of the target protein. Sumoylation is largely characterized as a modification of transcription factors and proteins involved in nuclear functions, and sumoylation of cell surface receptors has not been reported. We recently discovered that the type I TGF- beta receptor, TbRI, is sumoylated, making us hypothesize that sumoylation regulates the function of this receptor, and consequently TGF-beta signaling and the cell's response to TGF-beta. After identifying the sumoylation site in TbRI, we also found that a point mutation in TbRI, which has been found in association with metastatic breast cancer, confers a lack of sumoylation to TbRI. This leads to the hypothesis that sumoylation of the TbRI affects autocrine TGF-beta signaling and is a determinant of the invasive behavior of carcinomas. We propose three aims to define the molecular mechanism of TbRI sumoylation and its role in the cellular responses to TGF-b and the behavior of cancer cells in vivo. Aim 1 will characterize the mechanism of sumoylation of TbRI, including a search to identify the responsible E3 SUMO ligase. Aim 2 will examine the effect of TbRI sumoylation on Smad and non-Smad signaling responses and the cell's proliferation and invasion responses to TGF-b. This Aim should also define functional differences between the "metastasis- associated" TbRI mutant, wild-type TbRI and a sumoylation-deficient TbRI point mutant in the signaling and cell behavior responses to TGF-b. Finally, Aim 3 will define the effect of TbRI sumoylation and of the "metastasis-associated" TbRI point mutation on the behavior of cancer cells and on cancer progression in vivo. The proposed studies should provide a basis for the characterization of the mechanism of the TGF- beta receptor sumoylation, its role in the cell's response to TGF-beta and in cancer cell behavior and cancer progression.