Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells.
Tissue transglutaminase promotes serotonin-induced AKT signaling and mitogenesis in pulmonary vascular smooth muscle cells.
复制标题
DOI：
10.1016/j.cellsig.2014.09.002
复制
发表时间：
2014-12
影响因子：
4.8
通讯作者：
Toksoz D
中科院分区：
文献类型：
--
作者：
Penumatsa K;Abualkhair S;Wei L;Warburton R;Preston I;Hill NS;Watts SW;Fanburg BL;Toksoz D
组织转谷氨酰胺酶2 （TG2）是一种多功能酶，通过转谷氨酰胺反应将蛋白质与单胺如5-羟色胺（5-羟色胺，5-HT）交联，并与病理生理血管反应有关。5-HT是肺动脉平滑肌细胞（PASMC）的一种丝裂原，与肺动脉高压发展背后的肺血管重塑有关。我们之前报道过5- ht诱导的PASMC增殖被TG2抑制剂单丹西甲胺（MDC）抑制；然而，人们对其机制知之甚少。在本研究中，我们假设TG2参与了5- ht诱导的PASMC信号通路。用不同浓度的抑制剂MDC预处理牛远端PASMC导致5- ht刺激的AKT和ROCK活化的不同抑制，而p-P38不受影响。浓度响应研究表明，在50 μM MDC时，AKT的活化受到显著抑制，同时AKT的下游靶点mTOR、p-S6激酶和p-S6也受到抑制。此外，siRNA缺失TG2导致5- ht诱导的AKT活化降低。免疫沉淀研究表明，5-HT处理导致血清素化AKT水平升高，并增加TG2-AKT复合物的形成，这被MDC抑制。TG2点突变体cdna在PASMC中的过表达表明，TG2 C277V转酰胺突变体减弱了5- ht诱导的AKT活化和5- ht诱导的PASMC有丝分裂。最后，5- ht诱导的AKT激活在SERT基因敲除的大鼠细胞中减弱，但在其野生型细胞中没有减弱。SERT抑制剂丙咪嗪同样阻断AKT的激活。这些结果表明，TG2通过促进AKT信号传导，可能通过其血清素化作用，促进5- ht诱导的远端PASMC增殖。综上所述，这些结果为TG2如何参与血管平滑肌重塑提供了新的见解。
Tissue transglutaminase 2 (TG2) is a multifunctional enzyme that cross-links proteins with monoamines such as serotonin (5-hydroxytryptamine, 5-HT) via a transglutamidation reaction, and is associated with pathophysiologic vascular responses. 5-HT is a mitogen for pulmonary artery smooth muscle cells (PASMC) that has been linked to the pulmonary vascular remodeling underlying pulmonary hypertension development. We previously reported that 5-HT-induced PASMC proliferation is inhibited by the TG2 inhibitor monodansylcadaverine (MDC); however, the mechanisms are poorly understood. In the present study we hypothesized that TG2 contributes to 5-HT-induced signaling pathways of PASMC. Pre-treatment of bovine distal PASMC with varying concentrations of the inhibitor MDC led to differential inhibition of 5-HT-stimulated AKT and ROCK activation, while p-P38 was unaffected. Concentration response studies showed significant inhibition of AKT activation at 50 μM MDC, along with inhibition of the AKT downstream targets mTOR, p-S6 Kinase and p-S6. Furthermore, TG2 depletion by siRNA led to reduced 5-HT-induced AKT activation. Immunoprecipitation studies showed that 5-HT treatment led to increased levels of serotonylated AKT and increased TG2-AKT complex formations which were inhibited by MDC. Overexpression of TG2 point mutant cDNAs in PASMC showed that the TG2 C277V transamidation mutant blunted 5-HT-induced AKT activation and 5-HT-induced PASMC mitogenesis. Finally, 5-HT-induced AKT activation was blunted in SERT genetic knock-out rat cells, but not in their wild-type counterpart. The SERT inhibitor imipramine similarly blocked AKT activation. These results indicate that TG2 contributes to 5-HT-induced distal PASMC proliferation via promotion of AKT signaling, likely via its serotonylation. Taken together, these results provide new insight into how TG2 may participate in vascular smooth muscle remodeling.
登录
查看更多内容
影响因子：
20.1
作者：
LEE, SL;WANG, WW;FANBURG, BL
通讯作者：
FANBURG, BL
组织转谷氨酰胺酶组成性地通过非经典途径激活HIF-1α启动子和核因子-κB。
影响因子：
3.7
作者：
Kumar S;Mehta K
通讯作者：
Mehta K
影响因子：
64.5
作者：
Walther, DJ;Peter, JU;Bader, M
通讯作者：
Bader, M
影响因子：
4.8
作者：
Antonyak, Marc A.;Li, Bo;Cerione, Richard A.
通讯作者：
Cerione, Richard A.
影响因子：
4.8
作者：
Boroughs, Lindsey K.;Antonyak, Marc A.;Cerione, Richard A.
通讯作者：
Cerione, Richard A.