Secretory pathway stress responses as possible mechanisms of disease involving Golgi Ca2+ pump dysfunction

Abstract

In mammalian tissues, uptake of Ca2+ and Mn2+ by Golgi membranes is mediated by the secretory pathway Ca2+- ATPases, SPCA1 and SPCA2, encoded by the ATP2C1 and ATP2C2 genes. Loss of one copy of the ATP2C1 gene, which causes SPCA1 haploinsufficiency, leads to squamous cell tumors of keratinized epithelia in mice and to Hailey-Hailey Disease, an acantholytic skin disease, in humans. Although the disease phenotypes resulting from SPCA1 haploinsufficiency in mice and humans are quite different, each species-specific phenotype is remarkably similar to those arising as a result of null mutations in one copy of the ATP2A2 gene, encoding SERCA2, the endoplasmic reticulum (ER) Ca2+ pump. SERCA2 haploinsufficiency, like SPCA1 haploinsufficiency, causes squamous cell tumors in mice and Darier’s Disease, also an acantholytic skin disease, in humans. The phenotypic similarities between SPCA1 and SERCA2 haploinsufficiency in the two species, and the general functions of the two pumps in consecutive compartments of the secretory pathway, suggest that the underlying disease mechanisms are similar. In this review we discuss evidence supporting the view that chronic Golgi stress and/or ER stress resulting from Ca2+ pump haploinsufficiencies leads to activation of cellular stress responses in keratinocytes, with the predominance of pro-apoptotic pathways (though not necessarily apoptosis itself) leading to acantholytic skin disease in humans and the predominance of pro-survival pathways leading to tumors in mice.

Discerning the Chemistry in Individual Organelles with Small‐Molecule Fluorescent Probes

“…[226] At the start of 2000, Tsien and co-workers reported the cell-permeable fluorescent turn-on probe Zinpyr-1 ( Scheme 42), which mainly localized within the Golgi apparatus or Golgi-apparatus-associated vesicles. [226] At the start of 2000, Tsien and co-workers reported the cell-permeable fluorescent turn-on probe Zinpyr-1 ( Scheme 42), which mainly localized within the Golgi apparatus or Golgi-apparatus-associated vesicles.…”

ATP2C1 gene mutations in Hailey–Hailey disease and possible roles of SPCA1 isoforms in membrane trafficking

“…48, 49 Null mutant embryos exhibited growth retardation, failure of neural tube closure, but normal hematopoiesis and cardiovascular development, resulting in embryonic lethality. 48 At subcellular level, golgi membranes of Spca1 −/− embryos were dilated, had fewer stacked leaflets, and were expanded in amount, consistent with increased golgi biogenesis.…”

The Secretory Pathway Calcium ATPase PMR-1/SPCA1 Has Essential Roles in Cell Migration during Caenorhabditis elegans Embryonic Development

“…In mice, cell adhesion appears normal, but cells show signs of Golgi dysfunction, which likely induces the high levels of apoptosis observed in the neural tube and mesenchyme [19]. Based on this genetic analysis, it is not evident that SPCA, which has a conserved role at the molecular level, has a similarly conserved role in development, although each phenotype may be the result of secretory pathway stress [25].…”