MAP3K4 promotes fetal and placental growth by controlling the receptor tyrosine kinases IGF1R/IR and Akt signaling pathway.
MAP3K4 promotes fetal and placental growth by controlling the receptor tyrosine kinases IGF1R/IR and Akt signaling pathway.
复制标题
MAP3K4通过控制受体酪氨酸激酶IGF1R/IR和AKT信号传导途径来促进胎儿和胎盘生长。
DOI：
10.1016/j.jbc.2022.102310
复制
发表时间：
2022-09
影响因子：
4.8
通讯作者：
Abell, Amy N.
中科院分区：
文献类型：
--
作者：
Perry, Charles H.;Mullins, Nathan A.;Sweileh, Razan B. A.;Shendy, Noha A. M.;Roberto, Patrick A.;Broadhurst, Amber L.;Nelson, Hannah A.;Miranda-Carboni, Gustavo A.;Abell, Amy N.
胎儿生长中断会对人类健康造成严重后果，包括胎儿和新生儿发病率和死亡率增加，以及潜在的终身健康问题。促进胎儿生长的分子机制代表了治疗和/或预防胎儿生长受限（FGR）的潜在治疗策略。在这里，我们确定了有丝分裂原活化蛋白激酶激酶4（MAP 3 K4）在促进胎儿和胎盘生长方面的一种以前未知的作用。我们证明MAP 3 K4激酶活性的失活导致FGR，部分原因是胎盘功能不全。值得注意的是，MAP 3 K4激酶失活的小鼠在断奶前表现出高度渗透性致死性，并且存活的成年小鼠的生长持续下降。此外，我们阐明了MAP 3 K4通过控制胰岛素样生长因子1受体（IGF 1 R）、胰岛素受体（IR）和Akt信号通路促进生长的分子机制。具体而言，在滋养层干细胞（TS）中MAP 3 K4激酶失活导致IGF 1 R和IR表达减少和Akt活化减少。我们观察到TS细胞中的这些变化也发生在通过培养的TS细胞的体外分化产生的分化的滋养层细胞中，以及在由TS细胞形成的胎盘组织中。此外，我们发现MAP 3 K4通过激活CREB结合蛋白（CBP）促进TS细胞中Igf 1 r转录本的表达来控制这一通路。在MAP 3 K4激酶失活的TS细胞中，由于CBP活性降低和组蛋白去乙酰化酶6表达和活性增加，Igf 1 r转录物受到抑制。总之，这些数据证明了MAP 3 K4通过控制IGF 1 R/IR和Akt信号通路的活性在促进胎儿和胎盘生长中的关键作用。
Disruption of fetal growth results in severe consequences to human health, including increased fetal and neonatal morbidity and mortality, as well as potential lifelong health problems. Molecular mechanisms promoting fetal growth represent potential therapeutic strategies to treat and/or prevent fetal growth restriction (FGR). Here, we identify a previously unknown role for the mitogen-activated protein kinase kinase kinase 4 (MAP3K4) in promoting fetal and placental growth. We demonstrate that inactivation of MAP3K4 kinase activity causes FGR due in part to placental insufficiency. Significantly, MAP3K4 kinase–inactive mice display highly penetrant lethality prior to weaning and persistent growth reduction of surviving adults. Additionally, we elucidate molecular mechanisms by which MAP3K4 promotes growth through control of the insulin-like growth factor 1 receptor (IGF1R), insulin receptor (IR), and Akt signaling pathway. Specifically, MAP3K4 kinase inactivation in trophoblast stem (TS) cells results in reduced IGF1R and IR expression and decreased Akt activation. We observe these changes in TS cells also occur in differentiated trophoblasts created through in vitro differentiation of cultured TS cells and in vivo in placental tissues formed by TS cells. Furthermore, we show that MAP3K4 controls this pathway by promoting Igf1r transcript expression in TS cells through activation of CREB-binding protein (CBP). In the MAP3K4 kinase–inactive TS cells, Igf1r transcripts are repressed because of reduced CBP activity and increased histone deacetylase 6 expression and activity. Together, these data demonstrate a critical role for MAP3K4 in promoting fetal and placental growth by controlling the activity of the IGF1R/IR and Akt signaling pathway.
登录
查看更多内容
影响因子：
3.4
作者：
Agrogiannis GD;Sifakis S;Patsouris ES;Konstantinidou AE
通讯作者：
Konstantinidou AE
影响因子：
3.7
作者：
Eaton, Malcolm;Davies, Alastair H.;Cross, James C.
通讯作者：
Cross, James C.
影响因子：
64.5
作者：
BAKER, J;LIU, JP;EFSTRATIADIS, A
通讯作者：
EFSTRATIADIS, A
影响因子：
4.8
作者：
Fujita, N;Sato, S;Tsuruo, T
通讯作者：
Tsuruo, T
影响因子：
23.9
作者：
Abell, Amy N.;Jordan, Nicole Vincent;Huang, Weichun;Prat, Aleix;Midland, Alicia A.;Johnson, Nancy L.;Granger, Deborah A.;Mieczkowski, Piotr A.;Perou, Charles M.;Gomez, Shawn M.;Li, Leping;Johnson, Gary L.
通讯作者：
Johnson, Gary L.