A Novel Mechanism by Which Tissue Transglutaminase Activates Signaling Events That Promote Cell Survival
A Novel Mechanism by Which Tissue Transglutaminase Activates Signaling Events That Promote Cell Survival
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DOI：
10.1074/jbc.m113.464693
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发表时间：
2014-04-04
影响因子：
4.8
通讯作者：
Cerione, Richard A.
中科院分区：
文献类型：
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作者：
Boroughs, Lindsey K.;Antonyak, Marc A.;Cerione, Richard A.
背景：组织转氨酶（tTG）促进肿瘤发生的各个方面，包括细胞存活。结果：在非转化细胞中异位表达的tTG触发涉及c-Src和PI 3-激酶的存活反应。结论：tTG通过c-Src依赖性机制激活PI 3-kinase，从而促进生存。重要性：这些发现表明tTG具有促进细胞存活的内在能力，并解释了它如何有助于肿瘤的发生。组织转氨酶（tTG）作为一种GTT酶和一种酰基转移酶，催化蛋白质交联的形成。tTG表达在人类癌症中经常上调，其中它涉及癌症进展的各个方面，包括细胞存活和化学抗性。然而，tTG与癌细胞背景下的其他蛋白质合作的程度，与其赋予细胞转化特征的内在能力相比，知之甚少。为了解决这个问题，我们询问了在非转化细胞背景中tTG的异位表达对细胞行为的影响。使用稳定表达Myc标记形式的tTG的NIH 3 T3成纤维细胞，我们发现tTG强烈地保护这些细胞免受血清饥饿诱导的凋亡，并触发PI 3-激酶/mTOR复合物1（mTORC 1）/p70 S6-激酶途径的激活。我们确定tTG与非受体酪氨酸激酶c-Src和PI 3-激酶形成复合物，并且用阻断tTG功能（单丹酰尸胺; MDC）或c-Src激酶活性（PP 2）的抑制剂处理细胞破坏了该复合物的形成，并阻止tTG激活PI 3-激酶途径。此外，用PP 2或抑制PI 3-激酶途径组分的抑制剂（包括PI 3-激酶（LY 294002）和mTORC 1（雷帕霉素））处理过表达tTG的成纤维细胞，消除了tTG促进的细胞存活。这些发现表明，tTG具有通过激活PI 3-激酶信号传导事件的新机制刺激细胞存活的内在能力，从而突出了tTG作为治疗人类癌症的潜在靶点。
Background: Tissue transglutaminase (tTG) promotes various aspects of oncogenesis, including cell survival. Results: Ectopically expressed tTG in non-transformed cells triggers a survival response that involves c-Src and PI3-kinase. Conclusion: tTG promotes survival by activating PI3-kinase through a c-Src-dependent mechanism. Significance: These findings demonstrate that tTG has an intrinsic capability to promote cell survival and explains how it contributes to oncogenesis.Tissue transglutaminase (tTG) functions as a GTPase and an acyl transferase that catalyzes the formation of protein cross-links. tTG expression is frequently up-regulated in human cancer, where it has been implicated in various aspects of cancer progression, including cell survival and chemo-resistance. However, the extent to which tTG cooperates with other proteins within the context of a cancer cell, versus its intrinsic ability to confer transformed characteristics to cells, is poorly understood. To address this question, we asked what effect the ectopic expression of tTG in a non-transformed cellular background would have on the behavior of the cells. Using NIH3T3 fibroblasts stably expressing a Myc-tagged form of tTG, we found that tTG strongly protected these cells from serum starvation-induced apoptosis and triggered the activation of the PI3-kinase/mTOR Complex 1 (mTORC1)/p70 S6-kinase pathway. We determined that tTG forms a complex with the non-receptor tyrosine kinase c-Src and PI3-kinase, and that treating cells with inhibitors to block tTG function (monodansylcadaverine; MDC) or c-Src kinase activity (PP2) disrupted the formation of this complex, and prevented tTG from activating the PI3-kinase pathway. Moreover, treatment of fibroblasts over-expressing tTG with PP2, or with inhibitors that inactivate components of the PI3-kinase pathway, including PI3-kinase (LY294002) and mTORC1 (rapamycin), ablated the tTG-promoted survival of the cells. These findings demonstrate that tTG has an intrinsic capability to stimulate cell survival through a novel mechanism that activates PI3-kinase signaling events, thus highlighting tTG as a potential target for the treatment of human cancer.