01971nas a2200337   4500008004100000020001400041245005600055210005300111260001600164300001100180490000600191520106000197653001901257653001601276653003401292653001301326653002201339653001001361653001101371653001101382100002201393700002201415700002001437700002001457700002701477700002101504700002401525700001801549700002101567856004501588       2019                        eng d  a2050-084X00aKLK3/PSA and cathepsin D activate VEGF-C and VEGF-D0 aKLK3PSA and cathepsin D activate VEGFC and VEGFD  c2019/05/17/  ae444780 v83 aVascular endothelial growth factor-C (VEGF-C) acts primarily on endothelial cells, but also on non-vascular targets, e.g. in the CNS and immune system. Here we describe a novel, unique VEGF-C form in the human reproductive system produced via cleavage by kallikrein-related peptidase 3 (KLK3), aka prostate-specific antigen (PSA). KLK3 activated VEGF-C specifically and efficiently through cleavage at a novel N-terminal site. We detected VEGF-C in seminal plasma, and sperm liquefaction occurred concurrently with VEGF-C activation, which was enhanced by collagen and calcium binding EGF domains 1 (CCBE1). After plasmin and ADAMTS3, KLK3 is the third protease shown to activate VEGF-C. Since differently activated VEGF-Cs are characterized by successively shorter N-terminal helices, we created an even shorter hypothetical form, which showed preferential binding to VEGFR-3. Using mass spectrometric analysis of the isolated VEGF-C-cleaving activity from human saliva, we identified cathepsin D as a protease that can activate VEGF-C as well as VEGF-D.10acancer biology10aCathepsin D10akallikrein-related peptidases10aKLK3/PSA10aLymphangiogenesis10amouse10aVEGF-C10aVEGF-D1 aJha, Sawan, Kumar1 aRauniyar, Khushbu1 aChronowska, Ewa1 aMattonet, Kenny1 aMaina, Eunice, Wairimu1 aKoistinen, Hannu1 aStenman, Ulf-Håkan1 aAlitalo, Kari1 aJeltsch, Michael  uhttps://elifesciences.org/articles/4447802239nas a2200193   4500008004100000020002200041245004600063210004100109250000600150260002900156300001200185520168900197100002001886700001901906700002101925700002201946700002701968856005001995       2015                        eng d  a978-3-934371-53-800aThe genetic causes of primary lymphedema.0 agenetic causes of primary lymphedema  a6  aColognebViavital Verlag  a210-2293 aEnglish:
Primary lymphedema can be treated, but not cured. In addition, their diagnosis is due to heterogeneous phenotypes often ambiguous. However, these problems can be tackled by identifying the edema-causing genetic lesions to yield unambiguous diagnoses and by developing specific treatments that address the underlying, molecular cause. New developments in molecular biology are providing the necessary tools for these tasks and in the recent years the genetic causes of many forms of primary lymphedema have been identified, notably by exome sequencing. For a significant proportion of lymphatic disorders multifactorial genetic causes are suspected.
This chapter provides an overview of the current knowledge on the genetic origin, the categorization as well as the molecular and biochemical causes of primary lymphedema.

German:
Primäre Lymphödeme sind behandelbar, aber nicht heilbar. Zudem ist die Diagnostik aufgrund heterogener Phänotypen oft nicht eindeutig. Um diese Probleme anzugehen, müssen die das Ödem verursachenden genetischen Ursachen gefunden, diagnostiziert und gezielt behandelt werden. Die hierzu notwendigen Techniken liefern die neuen Entwicklungen in der Molekularbiologie. Insbesondere durch die Technik der Exom-Sequenzierung wurden in den letzten Jahren die genetischen Ursachen vieler primärer Lymphödeme identifiziert. Für einen weiteren großen Anteil dieser Erkrankungen werden multifaktorielle genetische Dispositionen vermutet.
Dieses Kapitel gibt einen Überblick über den derzeitigen Kenntnisstand der genetischen Ursachen, der Kategorisierung sowie der molekularbiologischen und biochemischen Grundlagen primärer Lymphödeme.1 aMattonet, Kenny1 aWilting, Jörg1 aJeltsch, Michael1 aWeissleder, Horst1 aSchuchhardt, Christian  uhttps://jeltsch.org/Mattonet2015a?language=en01275nas a2200157   4500008004100000022001400041245006700055210006300122260001200185300001000197490000700207520079300214100002001007700002101027856006901048       2015                        eng d  a1433-525500aHeterogeneity of the origin of the lymphatic system. [German].0 aHeterogeneity of the origin of the lymphatic system German  c12/2015  a84-880 v193 aThe question “How does the lymphatic system develop?” may be a simple one, but it is fundamental to our understanding of lymphatic malformations in children and the regeneration of lymphatics in adults. The question is by no means new and was already explored in the early 20 century. This resulted in a long-lasting controversy, which until recently had been far from being settled. The interest in the lymphatic system has greatly increased in recent years due to its implications in a variety of diseases. Several studies published this year address the heterogeneity of lymphatic endothelial cell development and unite previous controversially discussed data in a coherent model. These remarkable results, as well as the studies that paved their way, are discussed in this review.1 aMattonet, Kenny1 aJeltsch, Michael  uhttp://www.dglymph.de/fileadmin/global/pdfs/LymphForsch_2-15.pdf02234nas a2200157   4500008004100000245010800041210007000149260001500219520165500234100003201889700001801921700002101939700002001960700002301980856007302003       2015                        eng d00aSubstrate efflux propensity is the key determinant of iPLA-β-mediated glycerophospholipid hydrolysised0 aSubstrate efflux propensity is the key determinant of iPLAβmedia  c2015/02/233 aA-type phospholipases (PLAs) are key players in glycerophospholipid (GPL)homeostasis and in mammalian cells, Ca2+-independent PLA-beta (iPLAβ) in particular has been implicated in this essential process.However, the regulation of this enzyme,which is necessary to avoid futile competition between synthesis and degradation, is not understood. Recently, we provided evidence that the efflux of the substrate molecules from the bilayer is the rate-limiting step in the hydrolysis of GPLs by some secretory nonhomeostatic) PLAs. To study if this is the case with iPLAβ as well a mass-spectrometric assay was employed to determine the rate of hydrolysis of multiple saturated and unsaturated GPL species in parallel using micelles or vesicle bilayers as the macrosubstrate. With micelles, the hydrolysis decreased with increasing acyl chain length independent of unsaturation and modest discrimination between acyl positional isomers was observed, presumably due to the differences in the structure of the sn1 and sn2 acyl binding sites of the protein. In striking contrast, no significant discrimination between positional isomers was observed with bilayers, and the rate of hydrolysis decreased with the acyl chain length logarithmically and far more than with micelles. These data provide compelling evidence that efflux of the substrate molecule from the bilayer, which also decreases monotonously with acyl chain length, is the rate-determining step in iPLAβ- mediated hydrolysis of GPLs in membranes. This finding is intriguing as it may help to understand how homeostatic PLAs are regulated and how degradation and biosynthesis are coordinated.1 aBatchu, Krishna, Chaithanya1 aHokynar, Kati1 aJeltsch, Michael1 aMattonet, Kenny1 aSomerharju, Pentti  uhttp://www.jbc.org/content/early/2015/02/23/jbc.M115.642835.abstract