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News From The Journal Of Clinical Investigation: Nov. 26, 2012

Parallel structure: Surprising similarities between kidney cells and neurons

The primary function of the kidneys is to filter the blood to remove waste and retain blood cells and proteins. Podocytes are specialized kidney cells that form a filtering structure known as a slit diaphragm. Disruption of the podocytes results in the enlargement of the slit diaphragm, causing nephrotic syndrome, and, eventually, renal failure. In this issue of the Journal of Clinical Investigation, researchers led by Shuta Ishibe and Pietro De Camilli at Yale University identified a protein network in podocytes that is responsible for maintaining the structural integrity of the slit diaphragms. By engineering mice that lack components of this protein network, Ishibe, Camilli, and colleagues found that they could block the formation of the slit diaphragms in the kidney. Interestingly, they found that this protein network is highly similar to the networks that mediate the development of neuronal synapses. In a companion commentary, Rosemary Sampogna and Qais Al-Awqati of Columbia University discuss how these findings alter our understanding of how slit diaphragms function in the ever-changing environment of the kidney.

TITLE: Role of dynamin, synaptojanin and endophilin in podocyte foot processes


ACCOMPANYING COMMENTARY TITLE: Taking a bite: endocytosis in the maintenance of the slit diaphragm


Mutations in αKlotho underlie a genetic form of rickets

FGF23, a growth factor that regulates the metabolism of calcium and phosphate, binds and activates a circulating receptor known as αKlotho (cKL). In a study published in the Journal of Clinical Investigation, researchers led by Kenneth White at Indiana University describe a patient with a chromosomal translocation that results in increased levels of αKlotho. The patient presented with rickets, low blood phosphate and calcium levels, and increased FGF23. To determine how αKlotho effects these changes, White and colleagues over-expressed cKL in mice and found that increased cKL resulted in enhanced FGF23 levels, decreased serum calcium and phosphate levels, low bone mineral content, and bone fractures. These data establish cKL as an important regulator of FGF23 production and phosphate metabolism and may have implications for the treatment of rickets. In a companion commentary, Harald Jüppner of Massachusetts General Hospital and Myles Wolf of the University of Miami discuss the role of FGF23 and αKlotho in mineral metabolism.

TITLE: Circulating αKlotho influences phosphate handling by controlling FGF23 production


ACCOMPANYING COMMENTARY TITLE: αKlotho: FGF23 coreceptor and FGF23-regulating hormone


USP44 helps cells double check chromosome segregation to prevent cancer

Tumor cells frequently have an irregular number of chromosomes, a condition known as aneuploidy. During cell division, checkpoint proteins stop the process of division to ensure that each daughter cell receives the appropriate number of chromosomes; defects in these checkpoints can cause aneuploidy. In this issue of the Journal of Clinical Investigation, researchers led by Paul Galardy at the Mayo Clinic in Rochester, MN, investigated the role of the checkpoint protein USP44. Using a mouse that lacks Usp44, they found that loss of USP44 prevents chromosomes from splitting evenly between daughter cells. Usp44-deficient mice were prone to spontaneous tumors, particularly in the lungs. Interestingly, low USP44 expression was correlated with poor prognosis in human lung cancer. In a companion commentary, Andrew Holland and Don Cleveland of the University of California, San Diego, discuss how theses findings impact our understanding of aneuploidy in cancer.

TITLE: USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis


ACCOMPANYING COMMENTARY TITLE: The deubiquitinase USP44 is a tumor suppressor that protects against chromosome missegregation


A sticky situation: researchers identify mucus-producing pathway in human airway cells

Inflammatory airway diseases such as asthma, COPD, and cystic fibrosis are associated with increased mucus production, but the molecular mechanisms that are responsible for mucus production in these diseases have not been determined. In this issue of the Journal of Clinical Investigation, researchers led by Michael Holtzman at Washington University of St. Louis defined a cell signaling pathway that enhances mucus production in the cells that line the human airway. The pathway, which involves the protein MAPK13, was also activated in human COPD patients. By inhibiting the activity of MAPK13, Holtzman and colleagues were able to reduce mucus production in human airway epithelial cells, suggesting that therapeutics targeting this pathway might be useful for the treatment of mucus production in humans.

TITLE: IL-13-induced airway mucus production is blocked by MAPK13 inhibition


Too much of a good thing: extra VEGF signaling slows tumor growth

Angiogenesis is the formation of new blood vessels. Establishment of a blood supply promotes tumor growth by providing access to oxygen and nutrients. Blood vessel development is largely mediated by a growth factor known as VEGF, which is targeted by anti-angiogenic therapies. In this issue of the Journal of Clinical Investigation, researchers led by Hong Chen at the University of Oklahoma identified two new proteins, epsin1 and epsin2, as important regulators of VEGF-stimulated angiogenesis. VEGF mediates angiogenesis by binding to a cell surface protein that instigates cellular changes that are required for blood vessel formation. Epsins are known to remove proteins from the cell surface, preventing their activation. Normally, the number of VEGF binding proteins (VEGFR) on the cell surface is tightly controlled, but Chen and colleagues found that mice lacking epsin1/2 had a greater number of VEGFR on the cell surface that led to extra VEGF signaling, abnormal tumor vasculature, and slower tumor growth. In a companion commentary, Nancy Klauber-DeMore of the University of North Carolina at Chapel Hill discusses how these findings could contribute to the development of epsin-based therapeutic targeting of tumor angiogenesis.

TITLE: Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling


ACCOMPANYING COMMENTARY TITLE: Are epsins a therapeutic target for tumor angiogenesis?


Mouse model explains how calcium channel mutation causes hypokalemic periodic paralysis

Hypokalemic periodic paralysis (HypoPP) is a skeletal muscle disorder that is characterized by episodes of severe muscle weakness and low serum potassium levels. It is caused be a genetic mutation in protein channels that pump calcium or sodium ions across the cell membrane, but it is unclear exactly how the calcium channel mutations cause muscle weakness. In this issue of the Journal of Clinical Investigation, researchers led by Stephen Cannon at the University of Texas Southwestern Medical Center created a mouse with the HypoPP-associated calcium channel mutation that had symptoms that were similar to human HypoPP. They found that the mutant calcium channel caused changes in the cellular membrane potential that altered the ability of the muscle fibers to contract. This study explains how an inherited mutation causes HypoPP in humans. In a companion commentary, Alfred George of Vanderbilt University discusses how inherited mutations in channels contribute to human disease.

TITLE: A calcium channel mutant mouse model of hypokalemic periodic paralysis


ACCOMPANYING COMMENTARY TITLE: Leaky channels make weak muscles


A tale of two heme transporters

Erythropoiesis, or the production of red blood cells, is a tightly regulated process that is sensitive to the balance of the proteins that form hemoglobin, heme and globin. The protein FLVCR1a is responsible for removing excess heme from cells and is essential for erythropoiesis. In this issue of the Journal of Clinical Investigation, researchers led by Emanuela Tolosano at the University of Torino in Italy identified another form of FLVCR1, FLVCR1b, that is responsible for exporting heme from the mitochondria of the cell, the location of heme production. By manipulating the expression of the FLVCR1 proteins in mice, Tolosano and colleagues found that FLVCR1b was required for erythropoiesis. FLVCR1a was not required for erythropoiesis, but was necessary to prevent excess bleeding, swelling, and skeletal abnormalities in the developing mouse embryo. These results indicate that mutations in the Flvcr1 gene may underlie diseases characterized by abnormal heme levels, such as Sideroblastic anemia. In a companion commentary, Mark Fleming of Children’s Hospital Boston discusses the role of heme transport in human physiology and disease.

TITLE: The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation


ACCOMPANYING COMMENTARY TITLE: Mitochondrial heme: an exit strategy at last



Journal of Clinical Investigation