Threonine 454 phosphorylation in Grainyhead-like 3 is important for its function and regulation by the p38 MAPK pathway

Krzywińska, Ewa; Zorawski, Marek D.; Taracha, Agnieszka; Kotarba, Grzegorz; Kikulska, Agnieszka; Mlacki, Michal; Kwiatkowska, Katarzyna; Wilanowski, Tomasz

doi:10.1016/j.bbamcr.2018.04.010

Cited by 2 publications

(6 citation statements)

References 62 publications

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“…Our subsequent investigations have proven this hypothesis to be true. 46 TP is a characteristic motif recognized by proline-directed protein kinases. We confirmed that the T454 residue undergoes phosphorylation in human keratinocytes.…”

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

“…Activation of p38 signaling in cells increases GRHL3 activity, and the T454 residue is important for the regulation of GRHL3 activity by the p38 MAPK pathway. 46…”

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

“…We also found several additional phosphorylation sites in the GRHL3 protein. 46 More such sites were identified in proteomic discovery-mode mass spectrometry studies, the results of which have been deposited in public databases, such as PhosphoSitePlus (www.phosphosite.org, accessed October 2019). 47 In addition to phosphorylation, the GRHL proteins can also be acetylated at several residues.…”

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

“…Post-translational modifications usually occur outside of structured domains; we noticed this trend in our earlier work. 46 However, with the sole exception of the T454 residue in GRHL3, none of these modifications have been investigated in any detail. For this reason, the associated modifying enzymes are not known, and there is a lack of clear evidence that any of these post-translational modifications drive carcinogenesis.…”

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

“…The location of the critical T454 phosphorylation site in the GRHL3 protein is marked above the bottom diagram. 46…”

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

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Grainyhead-like transcription factors in cancer – Focus on recent developments

Kotarba

Taracha-Wisniewska

Wilanowski

2020

Exp Biol Med (Maywood)

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The role of grainyhead-like transcription factors in cancer has been widely investigated by the scientific community. However, some of its aspects do not seem to be adequately appreciated, and these are the topic of our article. In addition to their well-documented role as tumor suppressors, in many cases the grainyhead-like proteins perform tumor-promoting functions, which make them potential drug targets. However, it is difficult to directly target transcription factors, which is why we recommend an alternative approach. The transcriptional transactivation activity of grainyhead-like transcription factors is regulated by phosphorylation, and protein kinases are much more feasible drug targets. Studying the phosphorylation of grainyhead-like proteins may thus allow to identify protein kinases regulating the activity of these factors, and design inhibitors of these kinases to indirectly regulate the activity of grainyhead-like transcription factors. There are many somatic mutations in the GRHL genes that occur during cancer development. These mutations are widely distributed across the GRHL loci, and these mutations are very rare. For this reason, they are unlikely to become targets of future therapies, nevertheless some of them may be driver mutations and studying them may provide important novel information about the regulation of functioning of the GRHL genes and proteins. Analogous information may be obtained by studying single nucleotide polymorphisms in GRHL genes that are associated with disease risk. Such polymorphisms may also prove useful in identifying individuals with an increased risk of a particular disease. Impact statement In the present article, we focus on relatively little appreciated aspects of involvement of the grainyhead-like (GRHL) transcription factors in cancer. These aspects are nevertheless very important for the functioning of GRHL proteins, as well as for cancer development. Some of the GRHL factors perform tumor-promoting functions in certain types of cancer, which makes them potential drug targets. Much information is available about somatic cancer mutations in the GRHL genes, yet there are very few analyses of these mutations in the scientific literature. The activity of GRHL transcription factors is controlled by phosphorylation, and we suggest that regulating their phosphorylation with specific protein kinases provides an alternative approach to modify the activity of GRHL proteins. Some single nucleotide polymorphisms (SNPs) in the GRHL genes are associated with disease risk. Studying such SNPs may yield new information about the functioning of GRHL genes and proteins, and may also allow to identify people with an increased risk of a particular disease.

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Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

“…Activation of p38 signaling in cells increases GRHL3 activity, and the T454 residue is important for the regulation of GRHL3 activity by the p38 MAPK pathway. 46…”

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

“…The location of the critical T454 phosphorylation site in the GRHL3 protein is marked above the bottom diagram. 46…”

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

See 3 more Smart Citations

Grainyhead-like transcription factors in cancer – Focus on recent developments

Kotarba

Taracha-Wisniewska

Wilanowski

2020

Exp Biol Med (Maywood)

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Non-Synonymous Variants in Fat QTL Genes among High- and Low-Milk-Yielding Indigenous Breeds

Topno

Kesarwani

Kushwaha

et al. 2023

Animals

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The effect of breed on milk components—fat, protein, lactose, and water—has been observed to be significant. As fat is one of the major price-determining factors for milk, exploring the variations in fat QTLs across breeds would shed light on the variable fat content in their milk. Here, on whole-genome sequencing, 25 differentially expressed hub or bottleneck fat QTLs were explored for variations across indigenous breeds. Out of these, 20 genes were identified as having nonsynonymous substitutions. A fixed SNP pattern in high-milk-yielding breeds in comparison to low-milk-yielding breeds was identified in the genes GHR, TLR4, LPIN1, CACNA1C, ZBTB16, ITGA1, ANK1, and NTG5E and, vice versa, in the genes MFGE8, FGF2, TLR4, LPIN1, NUP98, PTK2, ZTB16, DDIT3, and NT5E. The identified SNPs were ratified by pyrosequencing to prove that key differences exist in fat QTLs between the high- and low-milk-yielding breeds.

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Threonine 454 phosphorylation in Grainyhead-like 3 is important for its function and regulation by the p38 MAPK pathway

Cited by 2 publications

References 62 publications

Grainyhead-like transcription factors in cancer – Focus on recent developments

Grainyhead-like transcription factors in cancer – Focus on recent developments

Non-Synonymous Variants in Fat QTL Genes among High- and Low-Milk-Yielding Indigenous Breeds

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