# MAP3K7

## Overview
MAP3K7, also known as TAK1, is a gene that encodes the mitogen-activated protein kinase kinase kinase 7, a serine/threonine kinase integral to various cellular signaling pathways. This kinase is a pivotal component of the MAPK signaling cascade, playing a crucial role in mediating inflammatory and immune responses, as well as regulating cell survival, proliferation, and differentiation. The protein encoded by MAP3K7 is activated through interactions with TAK1-binding proteins (TAB1, TAB2, and TAB3) and is involved in the activation of the IKK complex, which is essential for NF-κB signaling. Additionally, MAP3K7 influences the JNK and p38 MAPK pathways, impacting transcription factors such as AP-1. Its involvement extends to TGF-β signaling, where it affects cytoskeletal organization and cell motility. Clinically, mutations in MAP3K7 are associated with various disorders, including cardiospondylocarpofacial syndrome and frontometaphyseal dysplasia, and its loss is implicated in cancer progression, particularly in prostate cancer and pediatric T-cell acute lymphoblastic leukemia (Micale2020Insights; Shim2005TAK1; Jillson2021MAP3K7).

## Structure
MAP3K7, also known as TAK1, is a serine/threonine kinase that plays a crucial role in the MAPK signaling pathway. The primary structure of MAP3K7 consists of an N-terminal kinase domain, a linker region, and a C-terminal coiled-coil domain (Wade2016Mutations). The kinase domain is essential for its enzymatic activity, while the coiled-coil domain is important for dimerization and autophosphorylation, which are critical for its function (Ouyang2014Transforming).

The secondary structure of MAP3K7 includes α-helices, particularly in the TAK1 binding domain (TAK1 BD) of TAB proteins, which are necessary for interaction despite low sequence homology (Hirata2017PostTranslational). The tertiary structure involves the folding of these domains to facilitate interactions with TAK1-binding proteins (TAB1, TAB2, and TAB3), which regulate its activation (Hirata2017PostTranslational).

MAP3K7 forms a quaternary structure by interacting with TAB proteins, forming a complex that is crucial for its activation and function in signaling pathways (Hirata2017PostTranslational). Post-translational modifications, such as phosphorylation at Ser-412, are essential for its activation and kinase activity (Ouyang2014Transforming). These modifications and interactions enable MAP3K7 to participate in various cellular processes, including stress response and cytokine signaling.

## Function
MAP3K7, also known as TAK1, is a serine/threonine kinase that plays a pivotal role in various signaling pathways, particularly those involved in inflammation and immune responses. In healthy human cells, MAP3K7 is crucial for the activation of the IKK complex, which is essential for NF-κB activation in response to inflammatory cytokines such as TNF-α and IL-1. This activation is vital for mediating cell survival and inflammatory responses, as it regulates the expression of genes involved in these processes (Shim2005TAK1).

MAP3K7 also functions upstream of JNK and p38 MAPK pathways, influencing transcription factors like AP-1, which are key in immune and inflammatory responses (Shim2005TAK1). In the context of TGF-β signaling, MAP3K7 is involved in cytoskeletal organization, cell adhesion, and migration, indicating its role in regulating cytoskeletal dynamics and cell motility (Micale2020Insights).

Additionally, MAP3K7 is implicated in the regulation of the cell cycle and autophagy, as it induces the expression of autophagy-related proteins such as LC3 and Beclin-1, which are crucial for maintaining normal cellular functions (Micale2020Insights). In macrophages, MAP3K7 is part of the MAPK signaling cascade, essential for transducing pathogen-associated signals and activating immune responses (Richter2016Induction).

## Clinical Significance
Mutations and alterations in the MAP3K7 gene are associated with several diseases and conditions. Cardiospondylocarpofacial syndrome (CSCFS) is linked to the MAP3K7 c.737-7A > G variant, which creates a new splice acceptor site, leading to an aberrant transcript and impaired TAK1-TAB1 complex formation. This affects downstream signaling pathways, including NF-kB and MAPK, and disrupts connective tissue homeostasis, contributing to clinical features such as heart, vertebral, and facial anomalies (Micale2020Insights). Another condition, frontometaphyseal dysplasia 2 (FMD2), is caused by heterozygous mutations in MAP3K7, such as the recurrent p.Pro485Leu mutation. These mutations result in increased TAK1 autophosphorylation and altered signaling pathways, affecting osteoblast differentiation and leading to skeletal deformities (Costantini2018Expansion; Wade2016Mutations).

In cancer, MAP3K7 loss is associated with prostate cancer progression and recurrence. It is an independent predictor of biochemical recurrence, particularly when there is joint loss with CHD1, and affects pathways related to cell adhesion and the cell cycle (Liu2007Deletion; Jillson2021MAP3K7). In pediatric T-cell acute lymphoblastic leukemia, MAP3K7 deletions are linked to a mature immunophenotype and affect cell proliferation independently of NF-κB signaling (Cordas2018MAP3K7).

## Interactions
MAP3K7, also known as TAK1, is a serine/threonine kinase that participates in various protein interactions crucial for its role in signaling pathways. It forms a complex with TAK1-binding proteins TAB1, TAB2, and TAB3, which is essential for its activation. TAB1 binds constitutively to the N-terminus of TAK1, while TAB2 and TAB3 bind to the C-terminus in a context-dependent manner, facilitating TAK1's activation through autophosphorylation (Hirata2017PostTranslational).

In the IL-1 signaling pathway, MAP3K7 interacts with TRAF6, linking it to the NIK-IKK cascade. This interaction is crucial for the activation of NF-κB, as TAK1 phosphorylates NIK, which subsequently activates IKK-a (NinomiyaTsuji1999The). TAB2 acts as an adaptor protein, mediating the activation of TAK1 by linking it to TRAF6, which is essential for IL-1-induced signaling (Takaesu2000TAB2).

MAP3K7 is also involved in the TGF-β1 signaling pathway, where it is targeted for degradation by the E3 ubiquitin ligase TRIM31. TRIM31 catalyzes K48-linked polyubiquitination of MAP3K7, leading to its proteasomal degradation, which negatively regulates the TGF-β1-mediated Smad and MAPK/NF-κB signaling pathways (Zhang2021The).


## References


[1. (Ouyang2014Transforming) Chuan Ouyang, Li Nie, Meidi Gu, Ailing Wu, Xu Han, Xiaojian Wang, Jianzhong Shao, and Zongping Xia. Transforming growth factor (tgf)-β-activated kinase 1 (tak1) activation requires phosphorylation of serine 412 by protein kinase a catalytic subunit α (pkacα) and x-linked protein kinase (prkx). Journal of Biological Chemistry, 289(35):24226–24237, August 2014. URL: http://dx.doi.org/10.1074/jbc.m114.559963, doi:10.1074/jbc.m114.559963. This article has 48 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1074/jbc.m114.559963)

[2. (Shim2005TAK1) Jae-Hyuck Shim, Changchun Xiao, Amber E. Paschal, Shannon T. Bailey, Ping Rao, Matthew S. Hayden, Ki-Young Lee, Crystal Bussey, Michael Steckel, Nobuyuki Tanaka, Gen Yamada, Shizuo Akira, Kunihiro Matsumoto, and Sankar Ghosh. Tak1, but not tab1 or tab2, plays an essential role in multiple signaling pathways in vivo. Genes & Development, 19(22):2668–2681, October 2005. URL: http://dx.doi.org/10.1101/gad.1360605, doi:10.1101/gad.1360605. This article has 600 citations.](https://doi.org/10.1101/gad.1360605)

[3. (Costantini2018Expansion) Alice Costantini, Carina Wallgren-Pettersson, and Outi Mäkitie. Expansion of the clinical spectrum of frontometaphyseal dysplasia 2 caused by the recurrent mutation p.pro485leu in map3k7. European Journal of Medical Genetics, 61(10):612–615, October 2018. URL: http://dx.doi.org/10.1016/j.ejmg.2018.04.004, doi:10.1016/j.ejmg.2018.04.004. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.ejmg.2018.04.004)

[4. (Hirata2017PostTranslational) Yusuke Hirata, Miki Takahashi, Tohru Morishita, Takuya Noguchi, and Atsushi Matsuzawa. Post-translational modifications of the tak1-tab complex. International Journal of Molecular Sciences, 18(1):205, January 2017. URL: http://dx.doi.org/10.3390/ijms18010205, doi:10.3390/ijms18010205. This article has 110 citations and is from a peer-reviewed journal.](https://doi.org/10.3390/ijms18010205)

[5. (Richter2016Induction) Erik Richter, Katharina Ventz, Manuela Harms, Jörg Mostertz, and Falko Hochgräfe. Induction of macrophage function in human thp-1 cells is associated with rewiring of mapk signaling and activation of map3k7 (tak1) protein kinase. Frontiers in Cell and Developmental Biology, March 2016. URL: http://dx.doi.org/10.3389/fcell.2016.00021, doi:10.3389/fcell.2016.00021. This article has 52 citations and is from a peer-reviewed journal.](https://doi.org/10.3389/fcell.2016.00021)

[6. (NinomiyaTsuji1999The) Jun Ninomiya-Tsuji, Kazuya Kishimoto, Atsushi Hiyama, Jun-ichiro Inoue, Zhaodan Cao, and Kunihiro Matsumoto. The kinase tak1 can activate the nik-iκb as well as the map kinase cascade in the il-1 signalling pathway. Nature, 398(6724):252–256, March 1999. URL: http://dx.doi.org/10.1038/18465, doi:10.1038/18465. This article has 979 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1038/18465)

[7. (Liu2007Deletion) Wennuan Liu, Bao-Li Chang, Scott Cramer, Patrick P. Koty, Tao Li, Jishan Sun, Aubrey R. Turner, Chris Von Kap-Herr, Peggy Bobby, Jianyu Rao, S. Lilly Zheng, William B. Isaacs, and Jianfeng Xu. Deletion of a small consensus region at 6q15, including themap3k7gene, is significantly associated with high-grade prostate cancers. Clinical Cancer Research, 13(17):5028–5033, September 2007. URL: http://dx.doi.org/10.1158/1078-0432.ccr-07-0300, doi:10.1158/1078-0432.ccr-07-0300. This article has 58 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/1078-0432.ccr-07-0300)

[8. (Takaesu2000TAB2) Giichi Takaesu, Satoshi Kishida, Atsushi Hiyama, Kyoko Yamaguchi, Hiroshi Shibuya, Kenji Irie, Jun Ninomiya-Tsuji, and Kunihiro Matsumoto. Tab2, a novel adaptor protein, mediates activation of tak1 mapkkk by linking tak1 to traf6 in the il-1 signal transduction pathway. Molecular Cell, 5(4):649–658, April 2000. URL: http://dx.doi.org/10.1016/s1097-2765(00)80244-0, doi:10.1016/s1097-2765(00)80244-0. This article has 495 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/s1097-2765(00)80244-0)

[9. (Jillson2021MAP3K7) Lauren K. Jillson, Leah C. Rider, Lindsey U. Rodrigues, Lina Romero, Anis Karimpour-Fard, Cera Nieto, Claire Gillette, Kathleen Torkko, Etienne Danis, Elizabeth E. Smith, Rosalie Nolley, Donna M. Peehl, M. Scott Lucia, James C. Costello, and Scott D. Cramer. Map3k7 loss drives enhanced androgen signaling and independently confers risk of recurrence in prostate cancer with joint loss of chd1. Molecular Cancer Research, 19(7):1123–1136, April 2021. URL: http://dx.doi.org/10.1158/1541-7786.mcr-20-0913, doi:10.1158/1541-7786.mcr-20-0913. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.1158/1541-7786.mcr-20-0913)

[10. (Zhang2021The) Jie Zhang, Lei Cao, Xiaohong Wang, Qian Li, Meng Zhang, Cheng Cheng, Liwen Yu, Fei Xue, Wenhai Sui, Shangwen Sun, Na li, Peili Bu, Bingyu Liu, Fei Gao, Junhui Zhen, Guohai Su, Cheng Zhang, Chengjiang Gao, Meng Zhang, and Yun Zhang. The e3 ubiquitin ligase trim31 plays a critical role in hypertensive nephropathy by promoting proteasomal degradation of map3k7 in the tgf-β1 signaling pathway. Cell Death & Differentiation, 29(3):556–567, September 2021. URL: http://dx.doi.org/10.1038/s41418-021-00874-0, doi:10.1038/s41418-021-00874-0. This article has 24 citations.](https://doi.org/10.1038/s41418-021-00874-0)

[11. (Micale2020Insights) Lucia Micale, Silvia Morlino, Tommaso Biagini, Annalucia Carbone, Carmela Fusco, Marco Ritelli, Vincenzo Giambra, Nicoletta Zoppi, Grazia Nardella, Angelantonio Notarangelo, Annalisa Schirizzi, Gianluigi Mazzoccoli, Paola Grammatico, Emma M. Wade, Tommaso Mazza, Marina Colombi, and Marco Castori. Insights into the molecular pathogenesis of cardiospondylocarpofacial syndrome: map3k7 c.737-7a > g variant alters the tgfβ-mediated α-sma cytoskeleton assembly and autophagy. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 1866(6):165742, June 2020. URL: http://dx.doi.org/10.1016/j.bbadis.2020.165742, doi:10.1016/j.bbadis.2020.165742. This article has 7 citations.](https://doi.org/10.1016/j.bbadis.2020.165742)

[12. (Wade2016Mutations) Emma M. Wade, Philip B. Daniel, Zandra A. Jenkins, Aideen McInerney-Leo, Paul Leo, Tim Morgan, Marie Claude Addor, Lesley C. Adès, Debora Bertola, Axel Bohring, Erin Carter, Tae-Joon Cho, Hans-Christoph Duba, Elaine Fletcher, Chong A. Kim, Deborah Krakow, Eva Morava, Teresa Neuhann, Andrea Superti-Furga, Irma Veenstra-Knol, Dagmar Wieczorek, Louise C. Wilson, Raoul C.M. Hennekam, Andrew J. Sutherland-Smith, Tim M. Strom, Andrew O.M. Wilkie, Matthew A. Brown, Emma L. Duncan, David M. Markie, and Stephen P. Robertson. Mutations in map3k7 that alter the activity of the tak1 signaling complex cause frontometaphyseal dysplasia. The American Journal of Human Genetics, 99(2):392–406, August 2016. URL: http://dx.doi.org/10.1016/j.ajhg.2016.05.024, doi:10.1016/j.ajhg.2016.05.024. This article has 55 citations.](https://doi.org/10.1016/j.ajhg.2016.05.024)

[13. (Cordas2018MAP3K7) David M. Cordas dos Santos, Juliane Eilers, Alfonso Sosa Vizcaino, Elena Orlova, Martin Zimmermann, Martin Stanulla, Martin Schrappe, Kathleen Börner, Dirk Grimm, Martina U. Muckenthaler, Andreas E. Kulozik, and Joachim B. Kunz. Map3k7 is recurrently deleted in pediatric t-lymphoblastic leukemia and affects cell proliferation independently of nf-κb. BMC Cancer, June 2018. URL: http://dx.doi.org/10.1186/s12885-018-4525-0, doi:10.1186/s12885-018-4525-0. This article has 9 citations and is from a peer-reviewed journal.](https://doi.org/10.1186/s12885-018-4525-0)