Phosphorylation of serine96 of histidine-rich calcium-binding protein by the Fam20C kinase functions to prevent cardiac arrhythmia

Pollak, Adam J.; Haghighi, Kobra; Kunduri, Swati S; Arvanitis, Demetrios A.; Bidwell, Philip A.; Liu, Guan Sheng; Singh, Vivek P.; Gonzalez, David J.; Sanoudou, Despina; Wiley, Sandra E.; Dixon, Jack E.; Kranias, Evangelia G.

doi:10.1073/pnas.1706441114

Cited by 37 publications

(44 citation statements)

References 33 publications

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“…Although it is possible that Fam20C is active during its transit route across the ER, we propose that a rather unique milieu in the Golgi is appropriate for Fam20C activity. Besides Ero1a and the recently reported sarcoplasmic reticulum histidine-rich calcium-binding protein (HRC) (Pollak et al, 2017), we identify several ER/Golgi-localized enzymes and chaperones that also interact with Fam20C (Fig 1 and Dataset EV1). Future studies are required to determine whether these proteins can be phosphorylated by Fam20C and can therefore participate in certain biological processes.…”

Section: Discussionmentioning

confidence: 74%

Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α

et al. 2018

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Family with sequence similarity 20C (Fam20C), the physiological Golgi casein kinase, phosphorylates numerous secreted proteins that are involved in a wide variety of biological processes. However, the role of Fam20C in regulating proteins in the endoplasmic reticulum (ER) lumen is largely unknown. Here, we report that Fam20C interacts with various luminal proteins and that its depletion results in a more reduced ER lumen. We further show that ER oxidoreductin 1α (Ero1α), the pivotal sulfhydryl oxidase that catalyzes disulfide formation in the ER, is phosphorylated by Fam20C in the Golgi apparatus and retrograde-transported to the ER mediated by ERp44. The phosphorylation of Ser145 greatly enhances Ero1α oxidase activity and is critical for maintaining ER redox homeostasis and promoting oxidative protein folding. Notably, phosphorylation of Ero1α is induced under hypoxia, reductive stress, and secretion-demanding conditions such as mammalian lactation. Collectively, our findings open a door to uncover how oxidative protein folding is regulated by phosphorylation in the secretory pathway.

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Section: Discussionmentioning

confidence: 74%

Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α

et al. 2018

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“…Collectively, our findings lead us to propose that phosphorylation of extracellular substrates by FAMK-1 is important in contexts where tissues undergo repeated mechanical strain. In light of this proposal, it is interesting to note that a link between Fam20C phosphorylation and prevention of cardiac arrhythmia has been reported in humans (Pollak et al, 2017).…”

Section: Discussionmentioning

confidence: 90%

Ancestral roles of the Fam20C family of secreted protein kinases revealed in C. elegans

Gerson-Gurwitz

Worby

Lee

et al. 2019

Journal of Cell Biology

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Fam20C is a secreted protein kinase mutated in Raine syndrome, a human skeletal disorder. In vertebrates, bone and enamel proteins are major Fam20C substrates. However, Fam20 kinases are conserved in invertebrates lacking bone and enamel, suggesting other ancestral functions. We show that FAMK-1, the Caenorhabditis elegans Fam20C orthologue, contributes to fertility, embryogenesis, and development. These functions are not fulfilled when FAMK-1 is retained in the early secretory pathway. During embryogenesis, FAMK-1 maintains intercellular partitions and prevents multinucleation; notably, temperature elevation or lowering cortical stiffness reduces requirement for FAMK-1 in these contexts. FAMK-1 is expressed in multiple adult tissues that undergo repeated mechanical strain, and selective expression in the spermatheca restores fertility. Informatic, biochemical, and functional analysis implicate lectins as FAMK-1 substrates. These findings suggest that FAMK-1 phosphorylation of substrates, including lectins, in the late secretory pathway is important in embryonic and tissue contexts where cells are subjected to mechanical strain.

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“…SIBLING proteins include OPN, DMP1, BSP, extracellular MEPE, and DSPP. Other proteins include specific extracellular matrix and transport proteins, proteases and protease inhibitors, plus biologically active peptide hormones, which regulate calcium phosphate precipitation as hydroxyapatite as well as BMP4 (Bone morphogenetic protein 4), which has a role in osteoclast differentiation and maturation [19,20,[61][62][63][64].…”

Section: Discussionmentioning

confidence: 99%

Two Novel FAM20C Variants in a Family with Raine Syndrome

Hernández-Zavala

Cortés-Camacho

Palma‐Lara

et al. 2020

Genes

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Two siblings from a Mexican family who carried lethal Raine syndrome are presented. A newborn term male (case 1) and his 21 gestational week brother (case 2), with a similar osteosclerotic pattern: generalized osteosclerosis, which is more evident in facial bones and cranial base. Prenatal findings at 21 weeks and histopathological features for case 2 are described. A novel combination of biallelic FAM20C pathogenic variants were detected, a maternal cytosine duplication at position 456 and a paternal deletion of a cytosine in position 474 in exon 1, which change the reading frame with a premature termination at codon 207 and 185 respectively. These changes are in concordance with a negative detection of the protein in liver and kidney as shown in case 2. Necropsy showed absence of pancreatic Langerhans Islets, which are reported here for the first time. Corpus callosum absence is added to the few reported cases of brain defects in Raine syndrome. This report shows two new FAM20C variants not described previously, and negative protein detection in the liver and the kidney. We highlight that lethal Raine syndrome is well defined as early as 21 weeks, including mineralization defects and craniofacial features. Pancreas and brain defects found here in FAM20C deficiency extend the functional spectrum of this protein to previously unknown organs.

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Phosphorylation of serine96 of histidine-rich calcium-binding protein by the Fam20C kinase functions to prevent cardiac arrhythmia

Cited by 37 publications

References 33 publications

Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α

Secretory kinase Fam20C tunes endoplasmic reticulum redox state via phosphorylation of Ero1α

Ancestral roles of the Fam20C family of secreted protein kinases revealed in C. elegans

Two Novel FAM20C Variants in a Family with Raine Syndrome

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