Journal
CELLULAR SIGNALLING
Volume 72, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2020.109632
Keywords
BAG3; CK1; Iporin; NCK; TurboID
Categories
Funding
- Wellcome Trust [097418/Z/11/Z, 097945/B/11/Z]
- MRC Next Generation Optical Microscopy [MR/K015869/1]
- Wellcome Trust [097418/Z/11/Z] Funding Source: Wellcome Trust
- MRC [MC_UU_00018/6, MR/K015869/1] Funding Source: UKRI
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The majority of mutations identified in patients with amelogenesis imperfecta have been mapped to FAM83H. As FAM83H expression is not limited to the enamel, how FAM83H contributes to amelogenesis is still largely unknown. We previously reported that members of the FAM83 family of proteins interact with and regulate the subcellular distribution of the promiscuous serine-threonine protein kinase CK1 family, through their shared Nterminal DUF1669 domains. FAM83H co-localises with CK1 isoforms to speckle-like structures in both the cytoplasm and nucleus. In this report, we show FAM83H, unlike other FAM83 proteins, interacts and colocalises with NCK1/2 tyrosine kinase adaptor proteins. This interaction is mediated by proline-rich motifs within the C-terminus of FAM83H, specifically interacting with the second and third SH3 domains of NCK1/2. Moreover, FAM83H pathogenic AI mutant proteins, which trigger C-terminal truncations of FAM83H, retain their interactions with CK1 isoforms but lose interaction with NCK1/2. These AI mutant FAM83H proteins acquire a nuclear localisation, and recruit CK1 isoforms to the nucleus where CK1 retains its kinase activity. As understanding the constituents of the FAM83H-localised speckles may hold the key to unravelling potential substrates of FAM83H-associated CK1 substrates, we employed a TurboID-based proximity labelling approach and uncovered several proteins including Iporin and BAG3 as potential constituents of the speckles.
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