MAP3K7

Phenotypes

Mouse phenotype:

Homozygous deletion of Tak1 is embryonic lethal at E10.5.

Subcellular localization

cilia, basal body

References: doi:10.1371/journal.pbio.3003902

Functional category

• Non-motile cilium / primary cilium
• Cardiac & muscle development
• Transcription regulation

Function

TGFB-activated kinase 1, the MAP3K that carries the non-canonical branch of TGFB/BMP signaling, operates at the primary cilium during cardiogenesis. Immunofluorescence of zebrafish heart sections at 3 dpf shows Tak1 concentrated at the basal region of cardiac primary cilia, with signal abolished in tak1 mutants, validating antibody specificity; ciliary Tak1 is also present in extracardiac tissues. In day 7 mouse gastruloids TAK1 localizes to primary cilia of NKX2-5-positive cardiac progenitors. In RPE-1 cells both endogenous and GFP-tagged TAK1 accumulate at the ciliary base and in some cells along the axoneme, verified against ciliary base, distal appendage (CEP164, Centrin-2) and IFT88 markers. During P19CL6 cardiomyocyte differentiation 3D imaging resolves TAK1 around the ciliary base and in a punctate pattern along the full ciliary length. TGFB1 and BMP2 stimulation drives TAK1 phosphorylation at T184/187 and S412, peaking at 60 min, with the increase localized to the ciliary base; the upstream regulators TAB2 and PKA-Calpha are required. Downstream, phosphorylated JNK1/2 accumulates at the ciliary base during differentiation and is lost on TAK1 inhibition. Frontometaphyseal dysplasia patient variants G168R and P485L show impaired recruitment to the ciliary base without loss of protein expression, linking ciliary mislocalization to disease. DOI 10.1371/journal.pbio.3003902