Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hailey-Hailey disease is an autosomal genetic disease caused by mutations in one of the two ATP2C1 alleles encoding the secretory pathway Ca²⁺/Mn²⁺-ATPase, hSPCA1. The disease almost exclusively affects epidermis, where it mainly results in acantholysis of the suprabasal layers. The etiology of the disease is complex and not well understood. We applied a yeast based complementation system to characterize fourteen disease-causing ATP2C1 missense mutations in presence or absence of wild type ATP2C1 or ATP2A2, encoding SERCA2. In our yeast model system, mutations in ATP2C1 affected Mn²⁺ transport more than Ca²⁺ transport as twelve out of fourteen mutations were unable to complement Mn²⁺ sensitivity while thirteen out of fourteen to some extent complemented the high Ca²⁺requirement. Nine out of fourteen mutations conferred a cold sensitive complementation capacity. In absence of a wild type ATP2C1 allele, twelve out of fourteen mutations induced an unfolded protein response indicating that in vivo folding of hSPCA1 is sensitive to disease causing amino acid substitutions and four of the fourteen mutations caused the hSPCA1 protein to accumulate in the vacuolar membrane. Co-expression of either wild type ATP2C1 or ATP2A2 prevented induction of the unfolded protein response and hSPCA1 mis-localization.
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PMID:Characterization of Hailey-Hailey Disease-mutants in presence and absence of wild type SPCA1 using Saccharomyces cerevisiae as model organism. 3249 69

TMEM165 was highlighted in 2012 as the first member of the Uncharacterized Protein Family 0016 (UPF0016) related to human glycosylation diseases. Defects in TMEM165 are associated with strong Golgi glycosylation abnormalities. Our previous work has shown that TMEM165 rapidly degrades with supraphysiological manganese supplementation. In this paper, we establish a functional link between TMEM165 and SPCA1, the Golgi Ca2+/Mn2+ P-type ATPase pump. A nearly complete loss of TMEM165 was observed in SPCA1-deficient Hap1 cells. We demonstrate that TMEM165 was constitutively degraded in lysosomes in the absence of SPCA1. Complementation studies showed that TMEM165 abundance was directly dependent on SPCA1's function and more specifically its capacity to pump Mn2+ from the cytosol into the Golgi lumen. Among SPCA1 mutants that differentially impair Mn2+ and Ca2+ transport, only the Q747A mutant that favors Mn2+ pumping rescues the abundance and Golgi subcellular localization of TMEM165. Interestingly, the overexpression of SERCA2b also rescues the expression of TMEM165. Finally, this paper highlights that TMEM165 expression is linked to the function of SPCA1.
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PMID:Investigating the functional link between TMEM165 and SPCA1. 3165 5

An important component of breast milk, calcium also appears as radiographically prominent microcalcifications in breast tissue that are often the earliest sign of malignancy. Ionic Ca²⁺ is a universal second messenger that controls a wide swathe of effector pathways integral to gene transcription, cell cycle control, differentiation, proliferation, cell migration, and apoptosis. Whereas prolonged elevation in resting Ca²⁺ levels drives proliferation to initiate and sustain tumor growth, depletion of calcium stores and attenuation of calcium influx pathways underlies tumor chemoresistance and evasion of apoptosis. This paradox of Ca²⁺ homeostasis highlights the challenge of targeting Ca²⁺ signaling pathways for breast cancer therapy. Furthermore, breast cancer is a heterogeneous disease classified into distinct subtypes based on tumor origin, stage of invasiveness and hormone receptor status. Classification is important for tailoring treatment, and in predicting clinical outcome or response to chemotherapy. There have been numerous reports of dysregulated expression, localization or activity of Ca²⁺ channels, regulators and pumps in breast cancer. An important aspect of these alterations is that they are specific to breast cancer subtype, as exemplified by a reciprocal switch in secretory pathway Ca²⁺-ATPase isoforms SPCA1 and SPCA2 depending on receptor status. In this review, we discuss the current knowledge of subtype specific changes in calcium channels and pumps, with a focus on functional insights that may inform new opportunities for breast cancer therapy.
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PMID:Subtype specific targeting of calcium signaling in breast cancer. 3178 87


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