Cell-autonomous regulation of epithelial cell quiescence by calcium channel Trpv6

Goldstein

et al. 2020

Preprint

Self Cite

The mechanisms governing cell quiescence-proliferation balance are poorly defined. Using a zebrafish model, here we report that Stc1a, a glycoprotein known as a hypocalcemic hormone, not only inhibits epithelial calcium uptake but also functions as a Ca2+-regulated switch controlling epithelial cell quiescence-proliferation balance. Among the 4 stc genes, only the stc1a expression is [Ca2+]-dependent. Genetic deletion of stc1a, but not stc2b, resulted in elevated body Ca2+ contents, ectopic Ca2+ deposit, body swelling, and premature death. Reducing epithelial calcium channel Trpv6-mediated Ca2+ uptake alleviated these phenotypes. Loss of Stc1a also promoted quiescent epithelial cells to re-enter the cell cycle. This action was accompanied by local IGF signaling activation and increased expression in papp-aa, a zinc metalloproteinase degrading Igfbp5a. Genetic deletion of papp-aa or igfbp5a abolished the elevated epithelial cell reactivation in stc1a−/− mutants. Likewise, inhibition of IGF1 receptor, PI3 kinase, Akt, and Tor signaling abolished epithelial cell reactivation. These results reveal that Stc1a plays dual roles in regulating epithelial calcium uptake and cell quiescence-proliferation balance and implicate Trpv6 and Papp-aa-Igfbp5a-IGF signaling in these functions.

Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 97%

Section: The Expression Of Stc1a Is Regulated By Ca 2+ Levelsmentioning

confidence: 95%

Section: Ca 2+ Uptakementioning

confidence: 97%

Section: Zebrafishmentioning

confidence: 99%

See 3 more Smart Citations

Stanniocalcin 1a is a Ca²⁺-regulated switch controlling epithelial cell quiescence-proliferation balance and Ca²⁺uptake

Goldstein

et al. 2020

Preprint

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ROS signaling-induced mitochondrial Sgk1 regulates epithelial cell plasticity

Rolling

et al. 2022

Preprint

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Many types of differentiated cells can reenter the cell cycle upon injury or stress. The mechanisms underlying this cell plasticity are still poorly understood. Here we investigated cell plasticity regulation using a zebrafish model, in which a population of differentiated epithelial cells are reactivated under a physiological context. We observed a robust and sustained increase in mitochondrial membrane potential in reactivated cells. Genetic and pharmacological perturbations show that elevated mitochondrial metabolism and ATP synthesis are critical for cell reactivation. Elevated mitochondrial metabolism increases mitochondrial ROS levels, which induces Sgk1 expression in the mitochondria. Deletion and inhibition of Sgk1 in zebrafish abolished cell reactivation. Similarly, ROS-dependent mitochondrial expression of SGK1 promotes S phase entry in human breast cancer cells. Mechanistically, Sgk1 coordinates mitochondrial activity with ATP synthesis by modulating F1Fo-ATP synthase phosphorylation. These findings suggest a conserved intramitochondrial signaling loop regulating epithelial cell renewal.

The metalloproteinase Papp-aa functions as a molecular switch linking IGF signaling to adaptive epithelial growth

Noer

et al. 2019

Preprint

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Human patients carrying inactivating mutations in the pregnancy-associated plasma protein-a2 (PAPP-A2) gene display short status and lower bone mineral density. The underlying mechanisms are not well understood. Using a zebrafish model, here we report a [Ca 2+ ]dependent mechanism by which Papp-aa regulates bone calcification via promoting Ca 2+transporting epithelial cell (ionocyte) reactivation. Ionocyte, normally quiescent, re-enter the cell cycle in response to low [Ca 2+ ] stress. Deletion of Papp-aa abolished ionocyte reactivation and resulted in a complete lack of calcified bone. Re-expression of Papp-aa, but not its active site mutant, rescued ionocyte reactivation. Inhibition of Papp-aa activity pharmacologically or by overexpressing STC1 or STC2 impaired ionocyte reactivation. Loss of Papp-aa expression or activity resulted in diminished IGF1 receptor-mediated Akt-Tor signaling activity in ionocytes and expression of a constitutively active Akt rescued ionocyte reactivation. Biochemically, Pappaa cleaved Igfbp5a, a high-affinity IGF binding protein specifically expressed in ionocytes. Under normal [Ca2+] conditions, the Papp-aa-mediated Igfbp5a proteolysis was suppressed and IGFs sequestered in the IGF/Igfbp5a complex. Forced release of IGFs from the complex was sufficient to activate the IGF-Akt-Tor signaling and promote ionocyte reactivation. These findings suggest that Papp-aa functions as a [Ca 2+ ]-regulated molecular switch linking IGF signaling to adaptive epithelial growth and bone calcification.