Abstract
The MAP3K1 is responsible for transmitting signals to activate specific MAP2K-MAPK cascades. Following the initial biochemical characterization, genetic mouse models have taken center stage to elucidate how MAP3K1 regulates biological functions. To that end, mice were generated with the ablation of the entire Map3k1 gene, the kinase domain coding sequences, or ubiquitin ligase domain mutations. Analyses of the mutants identify diverse roles that MAP3K1 plays in embryonic survival, maturation of T/B cells, and development of sensory organs, including eye and ear. Specifically in eye development, Map3k1 loss-of-function was found to be autosomal recessive for congenital eye abnormalities, but became autosomal dominant in combination with Jnk and RhoA mutations. Additionally, Map3k1 mutation increased eye defects with an exposure to environmental agents such as dioxin. Data from eye developmental models reveal the nexus role of MAP3K1 in integrating genetic and environmental signals to control developmental activities. Here, we focus the discussions on recent advances in understanding the signaling mechanisms of MAP3K1 in eye development in mice and in sex differentiation from human genomics findings. The research works featured here lead to a deeper understanding of the in vivo signaling network, the mechanisms of gene–environment interactions, and the relevance of this multifaceted protein kinase in disease etiology and pathogenesis.
Highlights
The mitogen-activated protein kinases (MAPKs) play pivotal roles in diverse cellular activities such as gene expression, cell proliferation, migration, survival, and death
We will summarize the current understanding of the physiological roles of MAP3K1, with emphases on two emerging topics: (1) eyelid development based on genetic studies in mice and (2) sex development and differentiation based on human genomics research
The kinase domain-deficient Map3k1∆KD/ ∆KD mice were born with an eye open at birth (EOB) phenotype, the same as that seen in the Map3k1−/− mice
Summary
The mitogen-activated protein kinases (MAPKs) play pivotal roles in diverse cellular activities such as gene expression, cell proliferation, migration, survival, and death. The RING domain has a typical Plant Homeodomain (PHD) motif, closely related to a RING finger with the specific spacing of cysteine and histidine residues This pathways, occasionally capable of regulating the ERK nuclear factor-κB (NF-κB). The SWIM domain mediates protein–protein interactions and binds to c-Jun. In vitro studies have alsoc-Jun revealed diverse putative signals and potential mechanisms to facilitate the subsequent ubiquitination and degradation [9]. A TOG domain has been identified in the region overlapping induction of MAPK activities interactions and cell migration by the growth factors. MAP3K1 oligomerization induces autophosphorylation at T1381 and T1393, leading tothe kinase activation [24,27], whereas oxidative stress causes the glutathionylation of MAP3K1 at C1238 to inhibit the kinase activity [28] In another instance, cells with genetic MAP3K1 ablation are defective in the induction of MAPK activities and cell migration by the growth factors TGFβ and EGF [29,30]. (1) eyelid development based on genetic studies in mice and (2) sex development and differentiation based on human genomics research
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