Alternative titles; symbolsJNK/SAPK-INHIBITORY KINASE; JIKDENDRITIC CELL-DERIVED PROTEIN KINASE; DPKHGNC Approved Gene Symbol: TAOK3Cytogenetic location: 12q24.2...
Alternative titles; symbols
HGNC Approved Gene Symbol: TAOK3
Cytogenetic location: 12q24.23 Genomic coordinates (GRCh38): 12:118,149,800-118,372,949 (from NCBI)
Mitogen-activated protein kinase (MAPK) cascades, including the ERK (see 601795), JNK/SAPK (see 601158), and p38 (see 600289) pathways, are the major signaling systems that link extracellular signals to intracellular responses. Thousand and one amino acid (TAO) kinases, such as TAOK3, are Ste20-related MAP3Ks (summary by Zhang et al., 2000).
▼ Cloning and Expression
By screening a human M426 fibroblast expression library with the bacterially expressed SH3 domain of eps8, Tassi et al. (1999) identified a TAOK3 cDNA, which the authors called JIK. The deduced 898-amino acid protein has a calculated molecular mass of 106 kD. The N-terminus encompasses a kinase domain including all 11 subdomains characteristic of serine/threonine kinases. The kinase domain shares sequence homology with members of the GCK (603166) subfamily of STE20-like kinases with an N-terminal catalytic domain and no p21-binding domain. The protein shares 57% sequence identity in the kinase domain with human STK3 (605030) and STK4 (604965) and 63% overall sequence identity with C. elegans Sulu. Northern blot analysis detected ubiquitous expression of a 4.4-kb transcript at similar levels in most tissues.
Zhang et al. (2000) cloned TAOK3, which they called DPK, from a dendritic cell cDNA library. In addition to the domains described by Tassi et al. (1999), they identified a zipper-binding and an ATP-binding region. They pointed out that the kinase domain exhibits significant homology to MAPKKKs, e.g., MAP3K1 (600982) and MAP3K2 (609487). Northern blot analysis detected ubiquitous expression of TAOK3, with highest expression in kidney, heart, and skeletal muscle. Expression was also detected in many leukemia cell lines, but not in colorectal, lung, or skin cancer cell lines.
Raman et al. (2007) showed that TAOK3, like TAOK1 (610266) and TAOK2 (613199), has SQ/TQ sites in its C-terminal domain, which serve as substrates for ATM and ATR phosphorylation.
Robbins (2015) mapped the TAOK3 gene to chromosome 12q24.23 based on alignment of the TAOK3 sequence (GenBank AF135158) with the genomic sequence (GRCh38).
▼ Gene Function
Tassi et al. (1999) found that TAOK3 activity and autophosphorylation was potently reduced after EGF (131530) stimulation. Coexpression of TAOK3 with JNK/SAPK in COS-7 cells showed that TAOK3 was unable to activate JNK/SAPK but reduced its basal activity. When TAOK3 and JNK were coexpressed in the presence of EGF, JNK activation by EGF was reduced. When TAOK3 and JNK were coexpressed in the presence of potent activators such as anisomycin and UV light, JNK activation was not affected by TAOK2. Coexpression studies with TAOK3 and the signaling kinases ERK2 (176948), ERK5 (602521), ERK6 (602399), p38 (600289), and SAPK4 (602899) showed that TAOK3 does not activate or have a significant negative effect on their enzymatic activity.
Using an in vitro kinase phosphorylation assay in mouse NIH3T3 fibroblasts, Zhang et al. (2000) found that overexpression of DPK could activate both the Erk1 (601795)/Erk2 pathway and the JNK/SAPK pathway in a dose-dependent manner, but did not affect the p38 pathway.
Raman et al. (2007) expressed dominant-negative TAOK3 mutant protein in HEK293 and HeLa cells that were treated with hydroxyurea, ionizing radiation, or UV light to induce the DNA damage response. P38 activation normally induced by these agents was reduced by 50% or more in the presence of the mutant TAOK3. TAOK3 knockdown by siRNA induced cell death within 48 hours. TAOK3 knockdown cells also diminished p38 activation in the presence of DNA damaging agents. After DNA damage from UV, more cells entered mitosis instead of arresting at the G2/M checkpoint after TAOK3 knockdown; inactive Cdc2 (116940), which accumulates after G2/M arrest, also decreased substantially. After radiation exposure and UV, wildtype TAOK3 was phosphorylated by ATM at ser324 and could inhibit p38 activation as well as the G2/M checkpoint. Mutation of ser24 to ala inhibited p38 activation and G2/M checkpoint in response to UV or radiation.