# FAM83H

## Overview
FAM83H is a gene located on chromosome 8 that encodes a protein belonging to the FAM83 family, characterized by the presence of a DUF1669 domain. This domain is crucial for interactions with casein kinase 1 (CK1) isoforms, particularly CK1α and CK1ε, and plays a significant role in the organization of keratin filaments within epithelial cells (Bozatzi2018The; Fulcher2018The). The FAM83H protein is involved in maintaining epithelial cell polarity and adhesion by regulating keratin filament dynamics, which is essential for processes such as cell migration and polarization (Kuga2013A). Mutations in the FAM83H gene are linked to autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI), a condition affecting tooth enamel, and the gene is also implicated in various cancers, where it is often upregulated and associated with poor prognosis (Snijders2017FAM83; Lee2008Mutational).

## Structure
The FAM83H protein is characterized by a distinct molecular structure that includes specific domains and motifs. The primary structure of FAM83H consists of 1179 amino acids, with the gene located on chromosome 8 (Huang2017Evolutionary). The N-terminal region of FAM83H contains the DUF1669 domain, which is involved in interactions with casein kinase 1 (CK1) isoforms. This domain includes a pseudo-phospholipase D (PLD)-like catalytic motif, although it lacks the elements necessary for actual PLD activity, classifying it as a pseudo-PLD (Bozatzi2018The).

The N-terminal region, specifically the first 287 amino acids, is crucial for the interaction with CK1, facilitated by a conserved motif (F270-X-X-X-F274-X-X-X-F278) (Wang2015Fam83h). The C-terminal region, particularly residues 1134-1139, is essential for the localization of FAM83H in the keratin cytoskeleton, termed the keratin-localization (KL) residues (Kuga2022The). Mutations in this region can lead to altered subcellular localization and function, as seen in amelogenesis imperfecta (Kuga2022The).

FAM83H can form dimers through its N-terminal PLD-like domain, suggesting a potential quaternary structure involving self-interaction (Wang2015Fam83h). The protein is also subject to phosphorylation by CK1, with phosphorylation sites primarily located at the C-terminus (Wang2015Fam83h). These structural features and modifications are critical for the protein's function and its role in disease mechanisms.

## Function
FAM83H is a gene that encodes a protein involved in the organization of keratin filaments, which are crucial for the structural stability of epithelial cells. In healthy human cells, FAM83H interacts with Casein Kinase 1 alpha (CK-1α) to mediate the rearrangement of keratin filaments. This interaction is essential for maintaining the filamentous state of keratins, as FAM83H recruits CK-1α to keratin filaments, influencing their structural organization (Kuga2013A). The protein acts as a linker, with its N-terminal region interacting with CK-1α and the C-terminal region with keratins, facilitating the proper distribution and function of keratin filaments (Kuga2013A).

FAM83H is primarily active in the cytoplasm, where it plays a role in maintaining epithelial cell polarity and adhesion by regulating keratin filament dynamics. This regulation is crucial for processes such as cell migration and polarization, which are important for normal cellular function and tissue integrity (Kuga2013A). The protein's involvement in these processes highlights its significance in maintaining the structural and functional integrity of epithelial tissues.

## Clinical Significance
Mutations in the FAM83H gene are primarily associated with autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI), a condition characterized by defects in tooth enamel. Individuals with ADHCAI have enamel that is initially of normal thickness but is soft and rapidly lost due to attrition after tooth eruption. The enamel is described as cheesy soft, light yellow, and sensitive to thermal changes. These mutations typically introduce premature translation termination codons in exon 5, leading to the hypocalcified AI phenotype (Lee2010FAM83H; Lee2008Mutational). Specific mutations result in truncated proteins that alter intracellular localization, contributing to the pathology (Lee2010FAM83H).

Beyond dental implications, FAM83H is implicated in various cancers. It is frequently upregulated in tumors, particularly due to increased DNA copy number, and is associated with poor prognosis in several cancers, including breast, head-and-neck, and pancreatic cancers (Zhuang2020FAM83H; Snijders2017FAM83). In pancreatic cancer, FAM83H overexpression correlates with worse prognosis and is linked to KRAS activation, promoting tumor progression and immune evasion (Zhuang2020FAM83H). FAM83H also plays a role in stabilizing β-catenin, which is crucial for cancer cell proliferation and invasion (Zhou2022LncRNA).

## Interactions
FAM83H interacts with casein kinase 1 (CK1) isoforms, particularly CK1α and CK1ε, through its DUF1669 domain, which is crucial for mediating these interactions. This domain, present in all FAM83 family members, allows FAM83H to anchor CK1 isoforms in specific subcellular compartments, influencing their localization and potentially their association with substrates (Fulcher2018The). The interaction between FAM83H and CK1 isoforms is mediated by a conserved structural motif within the DUF1669 domain, and mutations in this motif can disrupt the interaction (Fulcher2018The).

FAM83H also plays a role in the organization of the keratin cytoskeleton in colorectal cancer cells. It interacts with CK1α, leading to the disassembly of keratin filaments, which is associated with the loss of epithelial cell polarity and the epithelial-mesenchymal transition (Kuga2013A). FAM83H recruits CK1α to nuclear speckles by interacting with SON, a scaffold protein, and this recruitment is dependent on the presence of an intact keratin cytoskeleton (Kuga2016Casein). These interactions suggest that FAM83H is involved in various cellular processes, including the regulation of CK1 isoforms and keratin filament organization.


## References


[1. (Snijders2017FAM83) Antoine M. Snijders, Sun‐Young Lee, Bo Hang, Wenshan Hao, Mina J. Bissell, and Jian‐Hua Mao. <scp>fam</scp>83 family oncogenes are broadly involved in human cancers: an integrative multi‐omics approach. Molecular Oncology, 11(2):167–179, January 2017. URL: http://dx.doi.org/10.1002/1878-0261.12016, doi:10.1002/1878-0261.12016. This article has 80 citations and is from a peer-reviewed journal.](https://doi.org/10.1002/1878-0261.12016)

[2. (Huang2017Evolutionary) Wushuang Huang, Mei Yang, Changning Wang, and Yaling Song. Evolutionary analysis of fam83h in vertebrates. PLOS ONE, 12(7):e0180360, July 2017. URL: http://dx.doi.org/10.1371/journal.pone.0180360, doi:10.1371/journal.pone.0180360. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.1371/journal.pone.0180360)

[3. (Zhou2022LncRNA) Min Zhou, Shutao Pan, Tingting Qin, Chunle Zhao, Taoyuan Yin, Yang Gao, Yuhui Liu, Zhenxiong Zhang, Yongkang Shi, Yu Bai, Jun Gong, Xingjun Guo, Min Wang, and Renyi Qin. Lncrna fam83h-as1 promotes the malignant progression of pancreatic ductal adenocarcinoma by stabilizing fam83h mrna to protect β-catenin from degradation. Journal of Experimental &amp; Clinical Cancer Research, September 2022. URL: http://dx.doi.org/10.1186/s13046-022-02491-2, doi:10.1186/s13046-022-02491-2. This article has 7 citations.](https://doi.org/10.1186/s13046-022-02491-2)

[4. (Bozatzi2018The) Polyxeni Bozatzi and Gopal P. Sapkota. The fam83 family of proteins: from pseudo-plds to anchors for ck1 isoforms. Biochemical Society Transactions, 46(3):761–771, June 2018. URL: http://dx.doi.org/10.1042/bst20160277, doi:10.1042/bst20160277. This article has 42 citations and is from a peer-reviewed journal.](https://doi.org/10.1042/bst20160277)

[5. (Kuga2013A) Takahisa Kuga, Hideaki Kume, Naoko Kawasaki, Misako Sato, Jun Adachi, Takashi Shiromizu, Isamu Hoshino, Takanori Nishimori, Hisahiro Matsubara, and Takeshi Tomonaga. A novel mechanism of keratin cytoskeleton organization through casein kinase iα and fam83h in colorectal cancer. Journal of Cell Science, January 2013. URL: http://dx.doi.org/10.1242/jcs.129684, doi:10.1242/jcs.129684. This article has 45 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1242/jcs.129684)

[6. (Zhuang2020FAM83H) H. Zhuang, C. Zhang, and B. Hou. Fam83h overexpression predicts worse prognosis and correlates with less cd8+ t cells infiltration and ras-pi3k-akt-mtor signaling pathway in pancreatic cancer. Clinical and Translational Oncology, 22(12):2244–2252, May 2020. URL: http://dx.doi.org/10.1007/s12094-020-02365-z, doi:10.1007/s12094-020-02365-z. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.1007/s12094-020-02365-z)

[7. (Fulcher2018The) Luke J. Fulcher, Polyxeni Bozatzi, Theresa Tachie-Menson, Kevin Z. L. Wu, Timothy D. Cummins, Joshua C. Bufton, Daniel M. Pinkas, Karen Dunbar, Sabin Shrestha, Nicola T. Wood, Simone Weidlich, Thomas J. Macartney, Joby Varghese, Robert Gourlay, David G. Campbell, Kevin S. Dingwell, James C. Smith, Alex N. Bullock, and Gopal P. Sapkota. The duf1669 domain of fam83 family proteins anchor casein kinase 1 isoforms. Science Signaling, May 2018. URL: http://dx.doi.org/10.1126/scisignal.aao2341, doi:10.1126/scisignal.aao2341. This article has 76 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1126/scisignal.aao2341)

[8. (Lee2008Mutational) Sook-Kyung Lee, Jan C-C. Hu, John D. Bartlett, Kyung-Eun Lee, Brent P-J. Lin, James P. Simmer, and Jung-Wook Kim. Mutational spectrum offam83h: the c-terminal portion is required for tooth enamel calcification. Human Mutation, 29(8):E95–E99, August 2008. URL: http://dx.doi.org/10.1002/humu.20789, doi:10.1002/humu.20789. This article has 49 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1002/humu.20789)

[9. (Kuga2016Casein) Takahisa Kuga, Hideaki Kume, Jun Adachi, Naoko Kawasaki, Maiko Shimizu, Isamu Hoshino, Hisahiro Matsubara, Youhei Saito, Yuji Nakayama, and Takeshi Tomonaga. Casein kinase 1 is recruited to nuclear speckles by fam83h and son. Scientific Reports, September 2016. URL: http://dx.doi.org/10.1038/srep34472, doi:10.1038/srep34472. This article has 27 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/srep34472)

[10. (Kuga2022The) Takahisa Kuga, Naoki Inoue, Kensuke Sometani, Shino Murataka, Minami Saraya, Rina Sugita, Toshinari Mikami, Yasunori Takeda, Masanari Taniguchi, Kentaro Nishida, and Nobuyuki Yamagishi. The conserved c-terminal residues of fam83h are required for the recruitment of casein kinase 1 to the keratin cytoskeleton. Scientific Reports, July 2022. URL: http://dx.doi.org/10.1038/s41598-022-16153-y, doi:10.1038/s41598-022-16153-y. This article has 2 citations and is from a peer-reviewed journal.](https://doi.org/10.1038/s41598-022-16153-y)

[11. (Wang2015Fam83h) Shih‐Kai Wang, Yuanyuan Hu, Jie Yang, Charles E. Smith, Amelia S Richardson, Yasuo Yamakoshi, Yuan‐Ling Lee, Figen Seymen, Mine Koruyucu, Koray Gencay, Moses Lee, Murim Choi, Jung‐Wook Kim, Jan C‐C. Hu, and James P. Simmer. Fam83h null mice support a neomorphic mechanism for human <scp>adhcai</scp>. Molecular Genetics &amp; Genomic Medicine, 4(1):46–67, September 2015. URL: http://dx.doi.org/10.1002/mgg3.178, doi:10.1002/mgg3.178. This article has 33 citations.](https://doi.org/10.1002/mgg3.178)

[12. (Lee2010FAM83H) S.-K. Lee, K.-E. Lee, T.-S. Jeong, Y.-H. Hwang, S. Kim, J.C.-C. Hu, J.P. Simmer, and J.-W. Kim. Fam83h mutations cause adhcai and alter intracellular protein localization. Journal of Dental Research, 90(3):377–381, November 2010. URL: http://dx.doi.org/10.1177/0022034510389177, doi:10.1177/0022034510389177. This article has 30 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1177/0022034510389177)