MAP3K4 promotes fetal and placental growth by controlling the receptor tyrosine kinases IGF1R/IR and Akt signaling pathway
Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:298 |
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| Enthalten in: |
The Journal of biological chemistry - 298(2022), 9 vom: 01. Sept., Seite 102310 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Perry, Charles H [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 29.09.2022 Date Revised 18.10.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2022.102310 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM344414639 |
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| 100 | 1 | |a Perry, Charles H |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a MAP3K4 promotes fetal and placental growth by controlling the receptor tyrosine kinases IGF1R/IR and Akt signaling pathway |
| 264 | 1 | |c 2022 | |
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| 500 | |a Date Completed 29.09.2022 | ||
| 500 | |a Date Revised 18.10.2022 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Akt/PKB | |
| 650 | 4 | |a MAP3K4 | |
| 650 | 4 | |a fetal growth restriction | |
| 650 | 4 | |a insulin receptor | |
| 650 | 4 | |a insulin-like growth factor | |
| 650 | 4 | |a insulin-like growth factor receptor | |
| 650 | 4 | |a placenta | |
| 650 | 4 | |a protein kinase | |
| 650 | 7 | |a Igf1r protein, mouse |2 NLM | |
| 650 | 7 | |a CREB-Binding Protein |2 NLM | |
| 650 | 7 | |a EC 2.3.1.48 |2 NLM | |
| 650 | 7 | |a Receptor, IGF Type 1 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Receptor, Insulin |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-akt |2 NLM | |
| 650 | 7 | |a EC 2.7.11.1 |2 NLM | |
| 650 | 7 | |a MAP Kinase Kinase Kinase 4 |2 NLM | |
| 650 | 7 | |a EC 2.7.11.25 |2 NLM | |
| 650 | 7 | |a Map3k4 protein, mouse |2 NLM | |
| 650 | 7 | |a EC 2.7.11.25 |2 NLM | |
| 650 | 7 | |a Histone Deacetylase 6 |2 NLM | |
| 650 | 7 | |a EC 3.5.1.98 |2 NLM | |
| 700 | 1 | |a Mullins, Nathan A |e verfasserin |4 aut | |
| 700 | 1 | |a Sweileh, Razan B A |e verfasserin |4 aut | |
| 700 | 1 | |a Shendy, Noha A M |e verfasserin |4 aut | |
| 700 | 1 | |a Roberto, Patrick A |e verfasserin |4 aut | |
| 700 | 1 | |a Broadhurst, Amber L |e verfasserin |4 aut | |
| 700 | 1 | |a Nelson, Hannah A |e verfasserin |4 aut | |
| 700 | 1 | |a Miranda-Carboni, Gustavo A |e verfasserin |4 aut | |
| 700 | 1 | |a Abell, Amy N |e verfasserin |4 aut | |
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