The members of the nuclear hormone receptor (NHR) family bind their cognate
ligands to regulate diverse physiological processes such as proliferation,
differentiation and PCD by modulating transcription of a distinct array of
genes. NHRs act via recruiting coactivators that are capable of modifying and
remodelling chromatin structure. One of the projects in our lab is to understand
the molecular mechanisms involved in hormone-mediated PCD by analysing the
transcriptional regulation of the genes involved in apoptosis. We use both
Drosophila and mammalian cells as experimental systems to study the function of
NHRs in PCD. Ultimately all developmental signals lead to histone modifications
such as methylation, acetylation, ubiquitination and phosphorylation, resulting
in chromatin remodelling and gene activation and/or repression. In diseases such
as cancer, enzymes that bring about these modifications are often deregulated.
We are identifying and cloning enzymes/proteins that regulate
methylation/demethylation of histones in Drosophila and mammalian cells. With
the recent discovery of the histone demethylase protein family, some of our
current work involves the analysis of new histone demethylases involved in
nuclear hormone mediated transcription, proliferation, differentiation and PCD
in Drosophila. We are also studying potential roles of these epigenetic
modifiers in cancer. We use cellular, molecular, proteomic and genetic
approaches to study the functions of these enzymes.
4. Nedd4 proteins in physiology and disease
Natasha Boase, Scott Townley and Jantina Manning
Collaborators: David Cook (University of Sydney), Philip Poronnik
(University of Queensland), Grigori Rychkov (University of Adelaide), Baoli Yang
(University of Iowa) and Roger Daly (Garvan Institute)
Aberrations in the ubiquitin system underpin the pathogenesis of many
diseases including malignancies, neurodegenerative disorders and
channelopathies. Ubiquitin-protein ligases (E3s) determine the substrate
specificity of the ubiquitination process. The Nedd4 family of E3s is
evolutionarily conserved and required for the ubiquitination of numerous
cellular targets involved in processes such as transcription, stability and
trafficking of plasma membrane proteins, and the degradation of misfolded
proteins. Nedd4 is a gene initially identified in our laboratory. Members of the
Nedd4-family can ubiquitinate a range of membrane proteins, resulting in their
internalisation and degradation. We have shown that Nedd4, and the closely
related protein Nedd4-2, interacts with and ubiquitinates the epithelial sodium
channel (ENaC). ENaC is required for sodium absorption across a range of
epithelial tissues such as the lungs, colon and kidney and is an important
regulator of blood sodium concentration. Ubiquitination of ENaC by Nedd4 and
Nedd4-2 leads to its internalisation and degradation. Defects in this process
disrupt sodium homeostasis and can cause hypertension. Our current focus is to
characterise the mechanisms of regulation of ENaC and other ion channels (such
as voltage-gated sodium channels) by Nedd4 and Nedd4-2.
Regulation of ENaC by Nedd4-2. When intracellular Na+
levels are low, various hormones activate Sgk1, Akt or PKA, which phosphorylate
Nedd4-2. 14-3-3 binds to phosphorylated Nedd4-2 to prevent its interaction with
ENaC, resulting in an increase in the levels of ENaC at the plasma membrane.
When intracellular Na+ is high, Nedd4-2 ubiquitinates ENaC, which
leads to its internalisation and degradation. In a collaborative study we have recently found that the loss of Nedd4 in
mice results in reduced IGF-1 and insulin signalling, reduced growth and
neonatal lethality. Nedd4-deficient cells show reduced mitogenic activity. This
appears to be due to increased levels of the adaptor protein Grb10 resulting in
IGF-1R mislocalization and inhibition of IGF-1 and insulin signalling. We are
now studying the mechanism of Grb10 regulation by Nedd4.
There is evidence to suggest that Nedd4 has additional cellular targets.
Thus, we are analysing additional phenotypes that may be associated with the
knockout of Nedd4.
Back to top
5. Ndfips as regulators of Nedd4 family members
Hazel Dalton, Loretta Dorstyn, Natalie Foot, Kristen Ho and Yew Ann
Leong
Collaborators: Seong Seng Tan (Howard Florey Institute) and Baoli Yang
(University of Iowa)
We have identified a number of Nedd4-interacting proteins. Two such proteins are Ndfip1 and Ndfip2, which display Golgi and endosomal localisation, suggestive of a role in protein trafficking. Based on our data, Ndfip1 and Ndfip2 are predicted to function as adaptor proteins that recruit Nedd4 family E3s to their substrates to provide specificity and regulatory complexity to the ubiquitination system.
Our recent work suggests that Ndfips regulate the divalent metal ion transporter DMT1, the primary non-heme iron transporter in mammals. DMT1 interacts with both Ndfip1 and Ndfip2, and this promotes DMT1 ubiquitination and degradation by the Nedd4-family ubiquitin ligase, WWP2 (see Figure). Consistent with these observations Ndfip1-/- mice show increased hepatic iron deposition, indicating an essential function of Ndfip1 in iron homeostasis. Given that misregulation of DMT1 is implicated in a number of human diseases, Ndfips and WWP2 could be potential targets for therapeutic intervention to control iron uptake and/or metabolism. Furthermore, mutations and variations in WWP2 and Ndfip genes may result in diseases of iron metabolism. Our current focus is to further characterise WWP2 and Ndfips to provide additional understanding of this novel mechanism of regulating iron transport.
Using Ndfip1-/- mice to show how Ndfip1 is involved
in iron homeostasis. Ndfip1-/- mice show increased levels of DMT1
in the liver (A-B) which is associated with iron loading (C). The ion transport
activity in primary hepatocytes is also increased in Ndfip1-/- mice
compared to wild type littermates (D). Back to top
Selected Recent Publications
2009
Hiwase DK, White DL, Powell JA, Saunders VA, Zrim SA, Frede AK, Guthridge MA, Lopez AF, D’Andrea RJ, To LB, Melo JV, Kumar S, Hughes TP. Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors. Leukemia In press.
Dorstyn L, Kumar S (2009) Putative functions of caspase-2. F1000 Biology Reports In press.
Denton D, Shravage B, Simin R, Baehrecke EH, Kumar S. Larval midgut destruction in Drosophila: Not dependent on caspases but suppressed by the loss of autophagy. Autophagy In press.
Kumar S (2009) Caspase 2 in apoptosis, DNA damage response and tumor suppression: enigma no more? Nature Rev. Cancer 9: 897-903.
Denton D, Shravage B, Simin R, Mills K, Berry DL, Baehrecke EH, Kumar S (2009) Autophagy, not apoptosis, is essential for midgut cell death in Drosophila. Current Biology 19: 1741-1746.
Yang B, Kumar S (2009) Nedd4 and Nedd4-2: Closely related ubiquitin-protein ligases with distinct physiological functions. Cell Death Differ. In press. (doi:10.1038/cdd.2009.84)
Howitt J, Putz U, Lackovic J, Doan A, Dorstyn L, Cheng H, Yang B, Chan-Ling T, Silke J, Kumar S, Tan S-S (2009) Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc. Natl. Acad. Sci. USA 106:15489-15494.
Kumar S, Dorstyn L (2009) Analyzing caspase activation and caspase activity in apoptotic cells. In: Apoptosis Methods and Protocols (eds. Peter Erhardt and Ambrus Toth). Humana Press Inc. NJ, USA. Methods in Molecular Biology 559: 3-17.
Galluzzi L, Aaronson SA, Abrams J, Alnemri ES, Andrews DW, Ashkenazi A, Baehrecke EH, Bazan NG, Blagosklonny MV, Blomgren K, Borner C, Bredesen DE, Brenner C, Castedo M, Cidlowski JA, Ciechanover A, Cohen GM, De Laurenzi V, Maria RD, Deshmukh M, Dynlacht BD, El-Deiry WS, Fulda S, Garrido C, Golstein P, De Maria R, Deshmukh M, Dynlacht BD, El-Deiry WS, Flavell RA, Fulda S, Garrido C, Golstein P, Gougeon M-L, Green DR, Gronemeyer H, Hajnoczky G, Hardwick JM, Hengartner M, Ichijo H, Jäättelä M, Kepp O, Kimchi A, Klionsky DJ, Knight RA, Kornbluth S, Kumar S, Levine B, Lipton SA, Lugli E, Madeo F, Malorni W, Marine J-C W, Martin SJ, Medema JP, Mehlen P, Melino G, Moll UM, Morselli E, Nagata S, Nicholson DW, Nicotera P, Nuñez G, Oren M, Penninger J, Pervaiz S, Peter ME, Piacentini M, Prehn JHM, Puthalakath H, Rabinovich G, Rizzuto R, Rodrigues CMP, Rubinsztein DC, Rudel T, Scorrano L, Simon H-U, Steller H, Tschopp J, Tsujimoto Y, Vandenabeele P, Vitale I, Vousden KH, Youle RJ, Yuan J, Zhivotovsky B, Kroemer G (2009) Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ. 16: 1093–1107.
Kochetkova M, Kumar S, McColl S (2009) The chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells. Cell Death Differ. 16: 664-673.
Ho LH, Taylor R, Cakouros D, Dorstyn L, Bouillet P, Kumar S (2009) A tumor suppressor function for caspase-2. Proc. Natl. Acad. Sci. USA 106: 5336-5341.
Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nature Rev. Mol. Cell Biol. 10: 398-409.
Lee I-H, Campbell CR, Song S-H, Day ML, Kumar S, Cook DI, Dinudom A (2009) The activity of the epithelial sodium channels is regulated by the caveolin-1 via a Nedd4-2 dependent mechanism. J. Biol. Chem. 284: 12663-12669.
Hiwase DK, White DL, Saunders V, Frede A, To LB, Kumar S, Melo JV, Hughes TP (2009) Short term intense Bcr-Abl kinase inhibition with nilotinib is adequate to trigger cell death in BCR-ABL+ cells. Leukemia 23: 1205-1206.
Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G (2009) Classification of cell death: Recommendations of the nomenclature committee on cell death 2009. Cell Death Differ. 16: 3-11.
2008
Dorstyn L, Kumar S (2008) A biochemical analysis of the activation of the Drosophila caspase DRONC. Cell Death Differ. 15: 461-470.
Cao XR, Lill NL, Boase N, Shi PP, Croucher D, Shan H, Qu J, Sweezer EM, Place T, Kirby PA, Daly RJ, Kumar S*, Yang B* (2008) Nedd4 controls animal growth by regulating IGF-1 signaling. Science Signaling 1: ra5. (* joint senior authors).
Ho LH, Dorstyn L, Lambrusco, L, Read SH, Kumar S (2008) Caspase-2 is required for cell death induced by cytoskeletal disruption. Oncogene 27: 3393-3404.
Denton D, Mills K, Kumar S (2008) Methods and protocols for studying cell death in Drosophila. Methods in Enzymology 446: 17-37.
Cakouros D, Mills K, Denton D, Daish T, Paterson A, Kumar S (2008) dLKR/SDH regulates hormone mediated histone arginine methylation and transcription of cell death genes. J. Cell Biol. 182: 481-495.
Manning JA, Colussi PA, Koblar SA, Kumar S (2008) Nedd1 expression as a marker of dynamic centrosomal localization during mouse embryonic development. Histochem. Cell Biol. 129: 751-764.
Hiwase DK, Saunders V, Hewett D, Frede A, Zrim S, Dang P, Eadie L, To LB, Melo J, Kumar S, Hughes TP, White DL (2008) Dasatinib cellular uptake and efflux in CML cells: Therapeutic implications Clin. Cancer Res. 14: 3881-3888.
Schuetz F, Kumar S, Poronnik P, Adams DJ (2008) Regulation of the voltage-gated K+ channels KCNQ2/3 and 3/5 by the serum- and glucocorticoid-regulated kinase (SGK-1). Am. J. Physiol. Cell Physiol. 295: C73-C80.
He Y, Hryciw DH, Carroll ML, Myers SA,Whitbread AK, Kumar S, Poronnik P, Hooper JD (2008) The ubiquitin-protein ligase Nedd4-2 differentially interacts with and regulates members of the Tweety family of chloride ion channels. J. Biol. Chem. 283: 24000-24010.
Foot NJ, Dalton HE, Shearwin-Whyatt LM, Dorstyn L, Tan SS, Yang, B, Kumar S (2008) Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood 112: 4268-4275.
Putz U, Howitt J, Lackovic J, Foot NJ, Kumar S, Silke J, Tan S-S (2008) Nedd4-family interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4-family proteins. J. Biol. Chem. 283: 32621-32627.
2007
Manning J, Kumar S (2007) NEDD1: Function in microtubule nucleation, spindle assembly and beyond. Int. J. Biochem. Cell Biol. 39: 7-11.
Doumanis J, Dorstyn L, Kumar S (2007) Molecular determinants of the subcellular localization of the Drosophila Bcl-2 homologues DEBCL and BUFFY. Cell Death Differ. 14: 907-915.
Dibbens LM, Ekberg J, Taylor I, Hodgson BL, Conroy S-J, Lensink IL, Kumar S, Zielinski MA, Harkin LA, Sutherland GR, Adams DJ, Berkovic SF, Scheffer IE, Mulley JC, Poronnik P (2007) NEDD4-2 as a candidate susceptibility gene for epileptic photosensitivity. Genes Brain Behav. 6: 750-755.
Kumar S (2007) Caspases and their many biological functions. Cell Death Differ. 14: 1-2.
Ekberg J, Schuetz F, Boase NA, Conroy S-J, Manning J, Kumar S, Poronnik P, Adams DJ (2007) Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by ubiquitination: Novel role for Nedd4-2. J. Biol. Chem. 282:12135-12142.
Sanchez-Perez A, Kumar S, Cook DI (2007) GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2. Biochem. Biophys. Res. Commun. 359: 611-615.
Lee I-H, Dinudom A, Sanchez-Perez A, Kumar S, Cook DI (2007) Akt mediates the effects of insulin on epithelial sodium channel by inhibiting Nedd4-2. J. Biol. Chem.282: 29866-29873.
Kumar S (2007) Caspase function in programmed cell death. Cell Death Differ. 14: 32-43.
2006
Fotia AB, Cook DI, Kumar S (2006) The ubiquitin-protein ligases Nedd4 and Nedd4-2 show similar ubiquitin-conjugating enzyme specificities. Int. J. Biochem. Cell Biol. 23: 472-479.
Rauh R, Dinudom A, Fotia AB, Paulides M, Kumar S, Korbmacher C, Cook DI (2006) Stimulation of the epithelial sodium channel (ENaC) by the serum- and glucocorticoid-inducible kinase (Sgk) involves the PY-motifs of the channel but is independent of sodium feedback inhibition. Pflug. Arch. Eur. J. Physiol. 452: 290–299.
Shearwin-Whyatt L, Dalton H, Foot N, Kumar S (2006) Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins. BioEssays 28: 617-628.
Dorstyn L, Kumar S (2006) A cytochrome c-free fly apoptosome. Cell Death Differ. 13: 1049- 1051.
Mills K, Daish, T, Harvey KF, Pfleger CM, Hariharan IK, Kumar S (2006) The Drosophila melanogaster Apaf-1 homologue ARK is required for most, but not all, programmed cell death. J. Cell Biol. 172: 809-815.
Sang Q, Kim MH, Kumar S, Bye N, Morganti-Kossman MC, Gunnersen J, Fuller S, Howitt J, Hyde L, Beissbarth T, Scott HS, Silke J, Tan SS (2006) Nedd4-WW domain-binding protein 5 (Ndfip1) is associated with neuronal survival after acute cortical brain injury. J. Neurosci. 26: 7234-7244.
Daish T, Kumar S (2006) Biology of caspases. In: Apoptosis, Cell Signaling and Human Diseases: Molecular Mechanisms Vol 2 (R. Srivastava, Editor). The Humana Press, Inc. pp 347-363.
2005
Mills K, Daish T, Kumar S (2005) The function of the Drosophila caspase DRONC in cell death and development. Cell Cycle 4:744-746.
Kilpatrick ZE, Cakouros D, Kumar S (2005) Ecdysone-mediated upregulation of the effector caspase DRICE is required for hormone-dependent apoptosis in Drosophila cells. J. Biol. Chem. 280: 11981- 11986.
2004
Daish T, Cakouros D, Kumar S (2003) Distinct promoter regions regulate spatial and temporal expression of the Drosophila caspase dronc. Cell Death Differ. 10: 1348-1356.
Cakouros D, Daish TJ, Mills K, Kumar S (2004) An arginine-histone methyl transferase, CARMER, coordinates ecdysone-mediated apoptosis in Drosophila cells. J. Biol. Chem. 279:18467-18471.
Cakouros D, Daish TJ, Kumar S (2004) Ecdysone receptor directly binds the promoter of the Drosophila caspase dronc regulating its expression in specific tissues. J. Cell Biol. 165: 631- 640.
Ekert PG, Read SH, Silke J, Marsden V, Kaufmann H, Hawkins CJ, Gerl R, Kumar S, Vaux DL (2004) Apaf-1, caspase-2 and caspase-9 accelerate apoptosis, but do not determine whether factor-deprived or drug-treated cells die. J. Cell Biol. 165: 835-842.
Murdaca J, Treins C, Monthouël-Kartmann MN, Pontier-Bres R, Kumar S, Van Obberghen E, Giorgetti-Peraldi S (2004) Grb10 prevents Nedd4-mediated VEGF receptor-2 degradation. J. Biol. Chem. 279: 26754-26761.
Fotia AB, Ekberg J, Cook DI, Adams DJ, Poronnik P, Kumar S (2004) Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2. J. Biol. Chem. 279: 28930-28935.
Kumar S, Cakouros D (2004) Transcriptional control of the core cell death machinery. Trends Biochem. Sci. 29: 193-199.
Kumar S (2004) Migrate, differentiate, proliferate or die: Pleiotropic functions of an apical “apoptotic caspase”. Science STKE 2004: pe49.
Shearwin-Whyatt LM, Brown DL, Wylie FG, Stow JL, Kumar S (2004) N4WBP5A (Ndfip2), a Nedd4-interacting protein, localizes to multivesicular bodies and the Golgi, and has a potential role in protein trafficking. J. Cell Sci. 117: 3679-3689.
Dinudom A, Fotia A, Lefkowitz RJ, Young JA, Kumar S, Cook DI (2004) The kinase Grk2 regulates the Nedd4/Nedd4-2 dependent control of epithelial Na+ channels. Proc. Natl. Acad. Sci. USA. 101: 11886-11890.
Baliga BC, Read SH, Kumar S (2004) The biochemical mechanism of caspase-2 activation. Cell Death Differ. 11: 1234-1241.
Dorstyn L, Mills K, Lazebnik Y, Kumar S (2004) The two cytochrome c species, DC3 and DC4, are not required for caspase activation and apoptosis in Drosophila cells. J. Cell Biol. 167: 405-410.
Chew SK, Akdemir F, Chen P, Lu, W-J, Mills K, Daish, T, Kumar S, Rodriguez A, Abrams JM (2004) The apical caspase, dronc, governs programmed and unprogrammed cell death in Drosophila. Developmental Cell 7: 897-907.
Daish TJ, Mills K, Kumar S (2004) Drosophila caspase DRONC is required for specific developmental cell death pathways and stress-induced apoptosis. Developmental Cell 7: 909-915.
Hryciw DH, Ekberg J, Lee A, Lensink IL, Kumar S, Guggino WB, Cook DI, Carol A. Pollock CA, Poronnik P (2004) Nedd4-2 functionally interacts with ClC-5: involvement in constitutive albumin endocytosis in proximal tubule cells. J. Biol. Chem. 279: 54996-55007.
Dorstyn L, Kumar S (2004) Programmed cell death in Drosophila melanogaster. In: When Cells Die II- A comprehensive evaluation of apoptosis and programmed cell death (R. A. Lockshin and Z. Zakeri eds.), John Wiley & Sons, Inc., New York, pp 79-97.
Kumar S (2004) Measurement of caspase activity in cells undergoing apoptosis. In: Apoptosis Methods and Protocols (H.J.M. Brady ed.), Methods in Molecular Biology 282:19-30.
2003
Baliga C, Kumar S (2003) The Apaf-1/cytochrome c apoptosome: an essential initiator of caspase activation or just a sideshow? Cell Death Differ. 10: 15-17.
Fotia A, Dinudom A, Shearwin KE, Koch J-P, Korbmacher C, Cook DI, Kumar S (2003) The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels. FASEB J. 17: 70-72.
Baliga BC, Colussi PA, Read SH, Dias MM, Jans DA, Kumar S (2003) Role of prodomain in importin-mediated nuclear localization and activation of caspase-2. J. Biol. Chem. 278: 4899-4905.
Kim TW, Hung C-F, Ling M, Juang J, He L, Hardwick JM, Kumar S, Wu T-C (2003) Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins. J. Clin. Invest. 112: 110-117.
Quinn L, Coomb M, Mills K, Daish T, Colussi P, Kumar S, Richardson H (2003) Buffy, a Drosophila Bcl-2 related protein, has anti-apoptotic and cell cycle inhibitory function. EMBO J. 22: 3568-3579.
Daish T, Cakouros D, Kumar S (2003) Distinct promoter regions regulate spatial and temporal expression of the
Drosophila caspase
dronc. Cell Death Differ. 10: 1348-1356.
2002
Shcherbik N, Kumar S, Haines DS (2002) Substrate proteolysis is inhibited by dominant-negative Nedd4 and Rsp5 mutants harboring alterations in WW domain 1. J. Cell Sci. 115: 1041-1048.
Harvey KF, Shearwin-Whyatt LM, Fotia A, Parton RG, Kumar S (2002) N4WBP5, a potential target for ubiquitination by the Nedd4 family of proteins, is a novel Golgi-associated protein. J. Biol. Chem. 277: 9307-9317.
Dorstyn L, Read S, Cakouros D, Huh JR, Hay BA, Kumar S (2002) The role of cytochrome c in caspase activation in Drosophila cells. J. Cell Biol. 156: 1089-1098.
O'Reilly LA, Ekert P, Harvey N, Marsden V, Cullen L, Vaux DL, Hacker G, Magnusson C, Pakusch M, Cecconi F, Strasser A, Huang DCS, Kumar S (2002) Caspase-2 is not required for thymocyte or neuronal apoptosis even though cleavage of caspase-2 is mediated by Apaf-1 and caspase-9. Cell Death Diff. 9: 832-841.
Cakouros D, Daish T, Martin D, Baehrecke EH, Kumar S (2002) Ecdysone-induced expression of the caspase Dronc during hormone dependent programmed cell death in Drosophila is regulated by Broad-Complex. J. Cell Biol. 157: 985-995.
Baliga BC, Kumar S (2002) Role of Bcl-2 family of proteins in malignancy. Hematol. Oncology. 20: 63-74.
Richardson H, Kumar S (2002) Death to flies: Drosophila as a model system to study programmed cell death. J. Immunol. Meth. 265: 21-38.
Konstas A-A, Shearwin-Whyatt LM, Fotia A, Degger B, Riccardi D, Cook DI, Korbmacher C, Kumar S (2002) Regulation of the epithelial sodium channel by N4WBP5A, a novel Nedd4/Nedd4-2-interacting protein. J. Biol. Chem. 277: 29406-29416.
Read SH, Baliga BB, Ekert P, Vaux DL, Kumar S (2002) A novel Apaf-1-independent putative caspase-2 activation complex. J. Cell Biol. 159: 739-745.
Kumar S, Vaux DL (2002) A Cinderella caspase takes center stage. Science 297: 1290-1291.
Selected earlier publication
Dinudom A, Harvey KF, Komwatana P, Jolliffe CN, Young JA, *Cook DI, *Kumar S (2001) The roles of the carboxyl termini of a-, b- and g-subunits of epithelial Na+ channels (ENaC) in regulating ENaC and in mediating its inhibition by cytosolic Na+. J. Biol. Chem. 276: 13744-13749. (*equal senior authors)
Harvey KF, Dinudom A, Cook DI, Kumar S (2001) The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel. J. Biol. Chem. 276: 8597-8601.
Doumanis J, Quinn L, Richardson H, Kumar S (2001) STRICA, a novel Drosophila caspase with an unusual serine/threonine-rich prodomain, interacts with DIAP1 and DIAP2. Cell Death Diff. 8: 387-394.
Harvey NL, Daish T, Mills K, Dorstyn L, Quinn LM, Read SH, Richardson H, Kumar S (2001) Characterization of the Drosophila caspase, DAMM. J. Biol. Chem. 276: 25342-25350.
Shearwin-Whyatt LM, Harvey NL, Kumar S (2000) Subcellular localization and CARD-dependent oligomerization of the death adaptor RAIDD. Cell Death Diff. 7: 155-165.
Kumar S, Doumanis J (2000) The fly caspases. Cell Death Differ. 7: 1039-1044.
Colussi PA, Quinn LM, Huang DCS, Coombe M, Read SH, Richardson H, Kumar S (2000) Debcl, a pro-apoptotic Bcl-2 homologue, is a component of the Drosophila cell death machinery. J. Cell Biol. 148: 703-714.
Jolliffe CN, Harvey KF, Haines BP, Parasivam G, Kumar S (2000) Identification of multiple proteins expressed in murine embryos as binding partners for the WW domains of the ubiquitin-protein ligase Nedd4. Biochem. J. 351: 557-565.
Quinn LM, Dorstyn L, Mills K, Colussi PA, Chen P, Coombe M, Abrams J, *Richardson H, *Kumar S (2000) An essential role for the caspase Dronc in developmentally programmed cell death in Drosophila. J. Biol Chem.275: 40416-40424. (*equal senior authors)
Kumar S, Colussi PA (1999) Prodomains-adaptors-oligomerisation: the pursuit of caspase activation in apoptosis. Trends Biochem. Sci. 24: 1-4.
Harvey KF, Dinudom A, Komwatana P, Jolliffe CN, Day ML, Parasivam G, Cook DI, Kumar S (1999) All three WW domains of murine Nedd4 are involved in the regulation of epithelial sodium channels by intracellular Na+. J. Biol. Chem. 274: 12525-12530.
Dorstyn L, Colussi PA, Quinn LM, Richardson H, Kumar S (1999) DRONC, an ecdysone-inducible Drosophila caspase. Proc. Natl. Acad. Sci. USA 96: 4307-4312.
Ishibashi H, Dinudom A, Harvey KF, Kumar S, Young JA, Cook DI (1999) Na+-H+ exchange in salivary secretary cells is controlled by an intracellular Na+ receptor. Proc. Natl. Acad. Sci. USA 96: 9949-9953.
Morrione A, Plant P, Valentinis B, Staub O, Kumar S, Rotin D and Baserga R (1999) mGrb10 interacts with Nedd4. J. Biol. Chem. 274: 24094-24099.
Dorstyn L, Read SH, Quinn LM, Richardson H, Kumar S (1999) DECAY, a novel Drosophila caspase related to mammalian caspase-3 and caspase-7. J. Biol. Chem. 274: 30778-30783.
Harvey KF, Kumar S (1999) Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions. Trends Cell Biol. 9: 166-169.
Kumar S (1999) Mechanisms of caspase activation in cell death. Cell Death Diff. 6: 1060-1066.
Dinudom A, Harvey KF, Komwatana P, Young JA, Kumar S, Cook DI (1998) Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+. Proc. Natl. Acad. Sci. USA 95: 7169-7173.
Butt AJ, Harvey NL, Parasivam G, Kumar S (1998) Dimerization and autoprocessing of the Nedd2 (caspase-2) precursor requires both the prodomain and the carboxyl terminal regions. J. Biol. Chem. 273: 6763-6768.
Harvey KF, Harvey NL, Michael JM, Parasivam G, Waterhouse N, Alnemri ES, Watters D, Kumar S (1998) Caspase-mediated cleavage of the ubiquitin-protein ligase Nedd4 during apoptosis. J. Biol. Chem. 273: 13524-13530.
Bird CH, Sutton VR, Sun J, Hirst CE, Novak A, Kumar S, Trapani JA, Bird PI (1998) Selective regulation of apoptosis: the cytotoxic lymphocyte serpin PI-9 protects against granzyme B-mediated apoptosis without perturbing the Fas cell death pathway. Mol. Cell. Biol. 18: 6387-6398.
Colussi PA, Harvey NL, Kumar S (1998) Prodomain-dependent nuclear localization of the caspase-2 (Nedd2) precursor: A novel function for a caspase prodomain. J. Biol. Chem. 273: 24535-24542.
Waterhouse NJ, Finucane D, Green DR, Elce JS, Kumar S, Alnemri E, Litwack G, Lavin MF, Watters D (1998) Calpain activation is upstream of caspases in irradiation-induced apoptosis. Cell Death Diff. 5: 1051-1061.
Colussi PA, Harvey NL, Shearwin-Whyatt LM, Kumar S (1998) Conversion of procaspse-3 to an autoactivating caspase by fusion to the caspase-2 prodomain. J. Biol. Chem. 273: 26566-26570.
Kumar S, Kinoshita M, Dorstyn L, Noda M (1997) Origin, expression and possible functions of the two alternatively spliced forms of the mouse Nedd2 mRNA. Cell Death Diff. 4: 378-387.
Kumar S, Harvey KF, Kinoshita M, Copeland NG, Noda M, Jenkins NA (1997) cDNA cloning, expression analysis and mapping of the mouse Nedd4 gene. Genomics 40: 435-443.
Kinoshita M, Kumar S, Mizoguchi A, Ide C, Kinoshita A, Haraguchi T, Hiraoka Y, Noda M (1997) Nedd5, a mammalian septin, is a novel cytoskeletal component interacting with actin-based structures. Genes Dev. 11: 1535-1547.
Harvey NL, Butt A, Kumar S (1997) Functional activation of Nedd2/ICH-1 (caspase-2) is an early process in apoptosis. J. Biol. Chem. 272: 13134-13139.
Kumar S, Lavin MF (1996) The ICE family of cysteine proteases as effectors of cell death. Cell Death Diff. 3: 255-267.
Song Q, Lees-Miller SP, Kumar S, Zhang N, Chan DW, Smith GCM, Jackson SP, Alnemri ES, Litwack G, Khanna KK, Lavin MF (1996) DNA-dependent protein kinase catalytic subunit: A target for an ICE-like protease in apoptosis. EMBO J. 15: 3238-3246.
Song Q, Burrows S, Lees-Miller S, Smith G, Jackson S, Kumar S, Trapani JA, Alnemri E, Litwack G, Lu H, Moss D, Lavin MF (1996) ICE-like protease cleaves DNA-dependent protein kinase in cytotoxic T-cell killing. J. Exp. Med. 184: 619-626.
Waterhouse N, Kumar S, Song Q, Strike P, Sparrow L, Dreyfuss G, Alnemri ES, Litwack G, Lavin M, Watters D (1996) Heteronuclear ribonucleoproteins C1 and C2, components of the spliceosome, are specific targets of interleukin-1beta-converting enzyme-like proteases in apoptosis. J. Biol. Chem. 271: 29335-29341.
Kumar S (1995) ICE-like proteases in apoptosis. Trends Biochem. Sci. 20: 198-202.
Kumar S, Matsuzaki T, Yoshida Y, Noda M (1994) Molecular cloning and biological activity of a novel developmentally regulated gene encoding a protein with transducin beta-like structure. J. Biol. Chem. 269: 11318-11326.
Kumar S, Kinoshita M, Noda M, Copeland NG, Jenkins NA (1994) Induction of apoptosis by mouse Nedd2 gene, which encodes a protein similar to the product of the Caenorhabditis elegans cell death gene ced-3 and the mammalian IL-1beta-converting enzyme. Genes Dev. 8: 1613-1626.
Kumar S, Yoshida Y, Noda M (1993) Cloning of a cDNA which encodes a novel ubiquitin-like protein. Biochem. Biophys. Res. Commun. 195: 393-399.
Kumar S, Tomooka Y, Noda M (1992) Identification of a set of genes with developmentally down-regulated expression in the mouse brain. Biochem. Biophys. Res. Commun. 185: 1155-1161.
See a PubMed listing of Professor Sharad Kumars's publications
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Loretta Dorstyn, Sonia Shalini, Balazs Bajka and Joey Puccini 
