Mutations in PMCA2 and hereditary deafness: A molecular analysis of the pump defect

Giacomello, Marta; Mario, Agnese De; Lopreiato, Raffaele; Primerano, Simona; Campeol, Mara; Brini, Marisa; Carafoli, Ernesto

doi:10.1016/j.ceca.2011.09.004

Cited by 30 publications

(23 citation statements)

References 25 publications

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“…T47D cell lines overexpressing wtPMCA2 were previously described (8). The Quick Change Site-Directed Mutagenesis Kit (Agilent) was used to change nucleotide 2075 of the mouse pT-REx-PMCA2w/b construct (8) from C to A, creating the T692K mutation (24). The sequence of the mutant construct was verified on both strands, and T47D cells were sequentially transfected with pcDNA6-TR (tetracycline-regulated repressor; Life Technologies) and the tet-regulated WT PMCA2, T692KPMCA2, or control expression vector.…”

Section: Methodsmentioning

confidence: 99%

“…To test whether the calcium pumping function of PMCA2 is required for HER2 signaling, we used a doxycycline-inducible system to overexpress, in T47D cells, equal amounts of wild-type PMCA2 or a mutant form (PMCA2T692K) that has been shown to traffic normally, but that cannot pump calcium (24) (Fig. 4 G and H and Fig.…”

Section: Pmca2 Regulates Breast Cancer Cell Growth and Tumor Formationmentioning

confidence: 99%

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PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer

Jeong

VanHouten

Dann

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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In the lactating mammary gland, the plasma membrane calcium ATPase2 (PMCA2) transports milk calcium. Its expression is activated in breast cancers, where high tumor levels predict increased mortality. We find that PMCA2 expression correlates with HER2 levels in breast cancers and that PMCA2 interacts with HER2 in specific actin-rich membrane domains. Knocking down PMCA2 increases intracellular calcium, disrupts interactions between HER2 and HSP-90, inhibits HER2 signaling, and results in internalization and degradation of HER2. Manipulating PMCA2 levels regulates the growth of breast cancer cells, and knocking out PMCA2 inhibits the formation of tumors in mouse mammary tumor virus (MMTV)-Neu mice. These data reveal previously unappreciated molecular interactions regulating HER2 localization, membrane retention, and signaling, as well as the ability of HER2 to generate breast tumors, suggesting that interactions between PMCA2 and HER2 may represent therapeutic targets for breast cancer.calcium pumps | ErbB2 | receptor internalization | HSP-90 | epidermal growth factor receptor P lasma membrane calcium ATPases (PMCAs) are a family of ion pumps that transport calcium out of cells and maintain low resting intracellular calcium levels (1-3). PMCA2 (gene symbol Atp2b2) is highly expressed in the apical membrane of mammary epithelial cells only during lactation, where it has been shown to transport calcium into milk (4-6). After weaning, PMCA2 expression rapidly decreases, contributing to the initiation of programmed cell death and mammary gland involution (7,8). PMCA2 is also expressed in breast cancers (8-10), and high levels of tumor PMCA2 expression predict increased mortality in patients (8).Approximately 25-30% of invasive breast cancers overexpress human epidermal growth factor receptor 2 (HER2) as a result of amplification of the ERBB2 kinase gene (11-13), and overexpression of HER2 causes breast tumors in mouse mammary tumor virus (MMTV)-Neu transgenic mice (14). HER2 functions as a heterodimer with other ERBB family members, most commonly pairing with EGFR or human epidermal growth factor receptor 3 (HER3) in breast cancers (11, 13). For reasons that remain poorly understood, in contrast to other ERBB family members, which are internalized and degraded after stimulation, HER2 remains on the cell surface and continues to signal for prolonged periods (12,15).In this study, we describe a previously unrecognized function for PMCA2: supporting active HER2 signaling and HER2-mediated tumor formation. Our data suggest that PMCA2 interacts with HER2 within specific membrane domains and is required for HER2 expression, membrane retention, and signaling.Results PMCA2 and HER2 Are Coexpressed in Breast Cancers. PMCA2 levels correlate with HER2 in breast tumors (8). To further explore potential interactions between PMCA2 and HER2, we analyzed their expression in a previously reported tissue microarray consisting of 652 breast cancers with a median 9 y of clinical follow-up (8, 16). Patients with the highest quartiles of ...

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Section: Methodsmentioning

confidence: 99%

Section: Pmca2 Regulates Breast Cancer Cell Growth and Tumor Formationmentioning

confidence: 99%

PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer

Jeong

VanHouten

Dann

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

112

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“…The inner ear and the eye are the only affected bodily structures, and symptoms are limited to the functions of these structures. In Usher syndrome the hair cells of the cochlea develop, but malfunction occurs either due to defective tip-links or defects in the structures responsible for ion circulation, necessary for the firing of nerve pulses (Boëda et al, 2002;van Wijk et al, 2004;Kremer et al, 2006;Giacomello et al, 2011). Possibly, individuals with USH of type 1 or 2, respectively, develop hearing as fetuses, but then become either profoundly deaf or develop a hearing impairment, as a result of their genetic condition.…”

Section: Deafblindnessmentioning

confidence: 99%

Cognitive capacities and composite cognitive skills in individuals with Usher syndrome type 1 and 2

Henricson

2015

Studies From the Swedish Institute for Disability Research

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“…Between 150 and 200 researchers now work there on the molecular etiology of various diseases. My laboratory at VIMM has recently identified and analyzed molecularly a genetic defect in isoform 2 of the PMCA pump in human hereditary deafness (68) and another genetic defect, this time in isoform 3 of the PMCA pump, in X-linked cerebellar ataxia (69). These new exciting forays have kept and still keep my interest in calcium as alive as in the times when I was a young postdoctoral fellow.…”

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confidence: 99%

Amarcord: I Remember

Carafoli

2013

Journal of Biological Chemistry

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Ja, Kalzium, das ist alles!-Otto Loewy (1959)I have tried to offer a historical account of a success story, as I saw it develop from the early times when it interested only a few aficionados to the present times when it has pervaded most of cell biochemistry and physiology. It is of course the story of calcium signaling. It became my topic of work when I was a young postdoctoral fellow at The Johns Hopkins University. I entered it through a side door, that of mitochondria, which had been my area of work during my earlier days in Italy. The 1960s and 1970s were glorious times for mitochondrial calcium signaling, but the golden period was not going to last. As I have discussed below, mitochondrial calcium gradually lost appeal, entering a long period of oblivion. Its fading happened as the general area of calcium signaling was instead experiencing a phase of explosive growth, with landmark discoveries at the molecular and cellular levels. These discoveries established that calcium signaling was one of the most important areas of cell biology. However, mitochondria as calcium partners were not dead; they were only dormant. In the 1990s, they were rescued from their state of neglect to the central position of the regulation of cellular calcium signaling, which they had once rightly occupied. Meanwhile, it had also become clear that calcium is an ambivalent messenger. Hardly anything important occurs in cells without the participation of the calcium message, but calcium must be controlled with absolute precision. This is an imperative necessity, which becomes unfortunately impaired in a number of disease conditions that transform calcium into a messenger of death.

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Mutations in PMCA2 and hereditary deafness: A molecular analysis of the pump defect

Cited by 30 publications

References 25 publications

PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer

PMCA2 regulates HER2 protein kinase localization and signaling and promotes HER2-mediated breast cancer

Cognitive capacities and composite cognitive skills in individuals with Usher syndrome type 1 and 2

Amarcord: I Remember

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