Bieth, J.G. Leukacyte elastase, in Handbook of Protealtic Enzymes (eds Barrett, A.J. Rawlings, N.D. & Woessner J.F.) 54-60 (Academic Press, San Diego, 1998).

Takahashi, H., Nukiwa T., Basset P., & Crystal R.G. Myelomonocytic cell lineage expression of the neutrophil elastase gene. J. Biol. Chem. 263, 2543-2547 (1988).

Sinha, S. Et al. Primary structure of human neutrophil elastase. Proc Natl Acad. Sci, USA, 2228-2232 (1987).

Takashi, H., et al. Structure of the human neutrophil elastase gene. J. Biol. Chem. 263, 14739-14747 (1988).

Bade, W., Meyer, E. Jr., & Powers, J.C. Human leukocyte and porcine pancreatic elastase; x-ray crystal structures, mechanism, substrate specificity, and mechanism-based inhibitors. Biochemistry 28, 1951-1963 (1989).

Navia, M.A., et al. Structure of human neutrophil elastase in complex with a peptide chloramethyl ketone inhibitor at 1.84A resolution. Proc. Natl Acad Sci. USA 86, 7-11(1989).

Cregge, R.J., et al. Inhibition of human neutrophil elastase 4, Design, synthesis x-ray crystallographic analysis, and structure-activity relationships for a series of P2-modified, orally active peptidyl pentafluorethyl ketones. J. Med. Chem. 41, 2461-2480(1998).

Hung, S.H., & Hedstrom, L. Converting trypsin to elastase: substitution of the S1 site and adjacent loops reconstitutes esterase specificty but not amidase activity. Protein Eng. 11, 669-673 (1998).

Whisstock, J., Lesk, A.M. & Carrell, R. Modeling of serpin-protease complexes; antithrombin-thrombin, a 1-antitrypsin (358Met - Arg)-Thrombin, a 1-antitrypsin (358Met - Arg)-trypsin, and antitrypsin-elastase. Proteins 26. 288-303 (1996).Rawlings, N.D. & Barrett, A.J. Families of serine peptidases. Methods Enzymol, 244, 19-61 (1994).

Greenberger JS, Sakakkeny MA, Humphries RK, Eaves CJ, Eckner RJ: Demonstration of permanent factor-dependent multipotential (erythroid/neutrophil/basophil) hematopoietic progenitor cell lines. Proc Natl Acad Sci USA 80:2931, 1983.

De Koning JP, Schelen AM, Dong F, van Buietenen C, Burgering BM, Bos JL, Lowenberg B, Touw IP: Specific involvement of tyrosine 764 of human granulocyte colony-stimulating factor receptor in signal transduction mediated by p145/She/GRB2 or p90/GRB2 complexes. Blood 87: 132, 1996.

Sadowski HB, Gilman MZ: Cell-free activation of a DNA-binding protein by epidermal growth factor. Nature 362:79, 1993.

Lamb P, Kessler LV, Suto C, Levy DE, Seidel HM, Stein RB, Rosen J: Rapid activation of proteins that interact with the interferon-y activation site in response to mnultiple cytokines. Blood 83:2063, 1994.

Wagner BJ, Hayes TE, Hoban CJ, Cochran BH: The SIF binding element confers sis/PDGF inducibility onto the c-fos promoter. EMBOJ9:4477, 1990.

Wang D, Stravopodis D, Teglund S, Kitazawa J, Inhle JN: Naturally occurring dominant negative variants of Stat5. Mol Cell Biol 16:6141, 1996.

Shimozaki K, Nakajima K, Hirano T, Nagata S: Involvement of STAT3 in the granuloctye colony-stimulating factor-induced differentiation of myeloid cells. J Biol Chem 272:25184, 1997.

Teglund S, McKay C, Schuetz E, van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN: Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93:841, 1998.

Callus BA, Mathey-Prevot B: Interleukin-3-ineduced activation of the JAK/STAT pathway is prolonged by proteasome inhibitors. Blood 91: 3182, 1998.

Davis JN, Rock CO, Cheng MC, Watson JB, Ashmun RA, Kirk H, Kay RJ, Roussel MF: Complementation of growth factor receptor-dependent mitogenic signaling by a truncated type I phosphatidylinositol 4-phosphate 5-kinase. Mol Cell Biol 17:7398, 1997.

Prado GN, Suzuki H, Wilkinson N, Cousins B, Navarro J: Role of the C-terminus of the interleukin 8 receptor in signal transduction and internalization. J Biol Chem 271:19186, 1996.

Tannenbaum J, Tanenbaum SW, Godman GC: The binding sites of cytochalasin D. II. Their relationship to hexose transport and to cytochalasin B. J Cell Physiol 91:239, 1977.

Dougherty RW, Dubay GR, Niedel JE: Dynamics of the diradyl-glycerol responses of stimulated phagocytes. J Biol Chem 264:1123, 1989.

Odai H, Sasaki K, Iwamatsu A, Hanazono Y, Tanaka T, Mitani K, Yazaki Y, Hirai H: The proto-oncogene product c-Cbl becomes tyrosine phosphorylated by stimulation with GM-CSF or Epo and constitutively binds to the SH3 domains of Grb2/Ash in human hematopoietic cells. J Biol Chem 270:10800, 1995.

Lachaal M, Rampal AL, Lee W, Shi Y, Jung CY: GLUTI transmembrane glucose pathway. Affinity labeling with a transportable D-glucose diazirine. J Biol Chem 271:5225, 1996.

Anichini E, Zamperini A, Chevanne M, Caldini R, Pucci M, Fibbi G, Del Rosso M: Interaction of urokinase-type plasminogen activator with its receptor rapidly induces activation of glucose transporters. Biochemistry 36:3076, 1997.

Holm PK, Hansen SH, Sandvig K, van Deurs B: Endocytosis of desmosomal plaques depends on intact actin filaments and leads to a nondegradative compartment. Eur J Cell Biol 62:362, 1993.

Lamaze C, Fujimoto LM, Yin HL, Schmid SL: The actin cytoskeleton is required for receptor-mediated endocytosis in mammalian cells. J Biol Chem 272:20332, 1997.

Shibata Y, Metzger WJ, Myrvik QN: Chitin particle-induced cell-mediated immunity is inhibited by soluble mannan: Mannose receptor-mediated phagocytosis initiates IL-12 production. J Immunol 159:2462, 1997.

Lowry MB, Duchemin AM, Robinson JM, Anderson CL: Functional separation of pseudopod extension and particle internalization during Fc gamma receptor-mediated phagocytosis. J Exp Med 187: 161, 1998.

Kirchhausen T, Bonifacino JS, Riezman H: Linking cargo to vesicle formation-Receptor tail interactions with coat proteins. Curr Opin Cell Biol 9:488, 1997.

Marks MS, Ohno H, Kirchhausen T, Bonifacino JS: Protein sorting by tyrosine-based signals: Adapting to the Ys and wherefores. Trends Cell Biol 7:124, 1997.

Meydan N, Grunberger T, Dadi H, Shahar M, Arpaia E, Lapidot Z, Leeder JS, Freedman M, Cohen A, Gazit A, Levitzki A, Roifman CM: Inhibition of acute lymphoblastic leukaemia by a Jak-2 inhibitor. Nature 379:645, 1996.

Takemoto S, Mulloy JC, Cereseto A, Migone TS, Patel BK, Matsuoka M, Yamaguchi K, Takatsuki K, Kamihira S, White JD, Leonard WJ, Waldmann T, Franchini G: Proliferation of adult T cell leukemia/lymphoma cells is associated with the constitutive activation of JAK/STAT proteins. Proc Natl Acad Sci USA 94: 13897, 1997.

Chai SK, Nichols GL, Rothman P: Constitutive activation of JAKs and STATs in BCR-Abl-expressing cell lines and peripheral blood cells derived from leukemic patients. J Immunol 159:4720, 1997.

Hayakawa F, Towatari M, Iida H, Wakao H, Kiyoi H, Naoe T, Saito H: Differential constitutive activation between STAT-related proteins and MAP kinase in primary acute myelogenous leukaemia. Br J Haematol 101:521, 1998.

Migone T-S, Lin J-X, Cereseto A, Mulloy JC, O’Shea JJ, Franchini G, Leonard WJ: Constitutively activated Jak-STAT pathway in T cells transformed with HTLV-I. Science 269:79, 1995.

Cao X, Tay A, Guy GR, Tan YH: Activation and association of Stat3 with Src in v-Src-transformed cell lines. Mol Cell Biol 16:1595, 1996.

Chaturvedi P, Sharma S, Reddy EP: Abrogation of interleukin-3 dependence of myeloid cells by the v-src oncogene requires SH2 and SH3 domains which specify activation of STATs. Mol Cell Biol 17:3295, 1997.

Turkson J, Bowman T, Garcia R, Caldenhoven E, de Groot RP, Jove R: Stat3 activation by Src induces specific gene regulation and is required for cell transformation. Mol Cell Biol 18:2545, 1998.

Bromberg JF, Horvath CM, Besser D, Lathem WW, Darnell JE Jr: Stat3 activation is required for cellular transformation by v-src. Mol Cell Biol 18:2553, 1998.

Onishi M, Nosaka T, Misawa K, Mui AL-F, Gorman D, McMahon M, Miyajima A, Kitamura T: Identification and characterization of a constitutively active STAT5 mutant that promotes cell proliferation. Mol Cell Biol 18:3871, 1998.

Fukunaga R, Ishizaka-Ideda E, Pan C-X, Seto Y, Nagata S: Functional domains of the granulocyte-colony stimulating factor receptor. EMBO J 10:2855, 1991.

Mu8rakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K, Hamaguchi M, Taga T, Kishimoto T: Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci USA 88:11349, 1991.

Ward AC, Monkhouse JL, Csar XF, Touw IP, Bello PA: The Src-like kinase Hck is activated by granulocyte colony-stimulating factor (G-CSF), and docks to the activated G-CSF receptor. Biochem Biophys Res Commun (in press).

Bashey A, Healy L, Marshall CJ: Proliferative but not nonproliferative responses to granulocyte-colony stimulating factor are associated with rapid activation of the p21ras/MAP kinase signalling pathway. Blood 83:949, 1994.

Nicholson SE, Novak U, Ziegler SF, Layton JE: Distinct regions of the granulocyte colony-stimulating factor receptor are required for tyrosine phosphorylation of the signaling molecules JAK2, Stat3, and p42,prr MAPK. Blood 86:3698, 1995.

Csar XF, Ward AC, Hoffmann BW, Guy GG, Hamilton JA: cAMP suppresses p21 ras and Raf-1 responses but not the Erk-1 response to granulocyte-colony-stimulating factor: possible Raf-1-independent activation of Erk-1. Biochem J 322:79, 1997.

Ward AC, Monkhouse JL, Hamilton JA, Csar XF: Direct binding of Shc, Grb2, SHP-2 and p40 to the murine granulocyte colony-stimulating factor receptor. Biochim Biophys Acta (in press).

Dong F, van Buitenen C, Pouwels K, Hoefsloot LH, Lowenberg B, Touw IP: Distinct cytoplasmic regions of the human granulocyte colony-stimulating factor receptor involved in induction of proliferation and maturation. Mol Cell Biol 13: 7774, 1993.

Hermans MHA, Ward AC, Antonissen C, Karis A, Lowenberg B, Touw IP: Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony-stimulating factor receptor gene associated with severe chronic neutropenia. Blood 92:32, 1998.

Dittrich E, Haft CR, Muys L, Heinrich PC, Graeve L: A di-leucine motif and an upstream serine in the interleukin-6(IL-6) signal transducer gp 130 mediate ligand-induced endocytosis and down-regulation of the IL-6 receptor. J Biol Chem 271:5487, 1996.

Nicola NA: Hemopoietic cell growth factors and their receptors. Annu Rev Biochem 58:45, 1989.

Demetri GD, Griffin JD: Granulocyte colony-stimulating factor and its receptor. Blood 78:2791, 1991.

Lieschke GJ, Grail D, Hodgson G, Metcalf D, Stanley E, Cheers C, Fowler KJ, Basu S, Zhan YF, Dunn AR: Mice lacking granulocyte colony-stimulating factor have chronic neutropenia, granulocyte and macrophage progenitor cell deficiency and imparied neutrophil mobilization. Blood 84: 1737, 1994.

Fukunga R, Ishizaka Ikeda E, Seto Y, Nagata S: Expression cloning of a receptor for murine granulocyte colony-stimulating factor. Cell 61:341, 1990.

Nicholson SE, Oates AC, Harpur AG, Ziemiecki A, Wilks AF, Layton JE: Tyrosine kinase JAK1 is associated with the granulocyte-colony-stimulating factor receptor and both become tyrosine phosphorylated after receptor activation. Proc Natl Acad Sci USA 91:2985, 1994.

Tian S-S, Lamb P, Seidel HM, Stein RB, Rosen J: Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. Blood 84:1760, 1994.

Nicholson SE, Starr R, Novak U, Hilton DJ, Layton JE: Tyrosine residues in the granulocyte colony-stimulating factor receptor (G-CSF-R) mediate G-CSF-induced differentiation of murine myeloid leukemic (M1)cells. J Biol Chem 271:26947, 1996.

Tian S-S, Tapley P, Sincich C, Stein RB, Rosen J, Lamb P: Multiple signaling pathways induced by granulocyte colony-stimulating factor involving activation of JAKs, STAT5, and/or STAT3 are required for regulation of three distinct classes of immediate early genes. Blood 88:4435, 1996.

Barge RM, de Koning JP, Pouwels K, Dong F, Lowenberg B, Touw IP: Tryptophan 650 of human granulocyte colony-stimulating factor (G-CSF) receptor, implicated in the activation of JAK2, is also required for G-CSF-mediated activation of signaling complexes of the p21ras route. Blood 87:2148, 1996.

De Koning JP, Dong F, Smith L, Schelen AM, Barge RM, van der Plas DC, Hoefsloot LH, Lowenberg B, Touw IP: The membrane-distal cytoplasmic region of human granulocyte colony-stimulating factor receptor is required for STAT3 but not STAT1 homodimer formation. Blood 87:1335, 1996.

Novak U, Ward AC, Hertzog, PJ, Hamilton JA, Paradiso L: Aberrant activation of JAK/STAT pathway components in response to G-CSF, interferon-alpha/beta and interferon-gamma in NFS-60 cells. Growth factors 13:251, 1996.

Shimoda K, Feng J, Murakami H, Nagata S, Watling D, Rogers NC, Stark GR, Kerr IM, Ihle JN. Jak1 plays an essential role for receptor phosphorylation and Stat activation in response to granulocyte colony-stimulating factor. Blood 90:597, 1997.

Ward AC, Hermans MHA, Smith L, van Aesch YM, Schelen AM, Antonissen C, Touw IP: Tyrosine-dependent and independent mechanisms of STAT3 activation by the human granulocyte colony-stimulating factor (G-CSF) receptor are differentially utilized depending on G-CSF concentration. Blood (in press).

Corey SJ, Burkhardt AL, Bolen JB, Geahlen RL, Tkatch LS, Tweardy DJ: Granulocyte colony-stimulating factor receptor signaling involves the formation of a three-component complex with Lyn and Syk protein-tyrosine kinases. Proc Natl Acad Sci USA 91:4683, 1994.

Corey SJ, Dombrosky-Ferlan PM, Zuo S, Krohn E, Donnenberg AD, Zorich P, Romero G, Takata M, Kurosaki T: Requirement of Src kinase for induction of DNA synthesis by granulocyte colony-stimulating factor. J Biol Chem 273:3230, 1998.

Kruglyak L, Daly MJ, Reeve-Daly MP & Lander, ES. Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum Genetics, 58, 1347-1363(1996).

Cottingham RW Jr., Idury RM & Schaffer AA. Faster sequential genetic linkage computations. Am. J. Hum. Genetics t3, 252-263 (1993).

Fasman KH, Letovsky SI, Li P, Cottingham RW & Kingsbury DT. The GDB Human Genome Database Anna 1997. Nucleic Adds Res. 25, 72-81 (1997).

Berger SP et al. Proteinase 3, the major autoantigen of Wegener’s granulomatosis, enhances IL-B production by endothelial cells in vitro. J. Am. Soc. Nephrol. 7, 694-701(1996).

Wakasugi K, & Schimmel P. Two distinct cytokines released from a human aminoacyl-tRNA synthetase. Science 284, 147-151 (1999).

Perimutter DH, Glover GI, Rivetna M, Schasteen, CS & Fallon RJ. Identification of a serpin-enzyme complex receptor on human hepatoma cells and human monocytes. Proc. Natl. Acad. Sci. USA 87, 3753-3757 (1990).

Belaaouaj A., et al. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nature Med. 4, 615-618 (1998).

LeBonniec BF., et al. Characterization of the P2 and P3 specificities of thrombin using fluorescence-quenched substrates and mapping of the subsites by mutagenesis. Biochemistry 35, 7114-7122 (1996).

Rawlings, ND., & Barrett AJ. Families of serine peptidases. Methods Enzymol, 244, 19-61(1994).

Maniatis T, Sambrook J, Fritsch E: Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 1989, p 16.30.

Munson P, Rodbard D: Ligand: A versatile computized approach for characterization of ligand-binding systems. Anal Biochem 107:220, 1980.

Dittrich E, Rose-John S, Gerhartz C, Mullberg J, Stoyan T, Yasukawa K, Heinrich PC, Graeve L: Identification of a region within the cytoplasmic domain of the interleukin-6 (IL-6) signal transducer gp130 important for ligand-ineduced endocytosis of the IL-6 receptor. J Biol Chem 269:1904, 1994.

Dittrich E, Haft C, Muys L, Heinrich P, Graeve L: A dileucine motif and an upstream serine in the interleukin-6(IL-6) signal transducer gp130 mediate ligand-induced endocytosis and down-regulation of the IL-6 receptor. J Biol Chem 271:5487, 1996.

Bonifacino J: Biosynthetic labeling of proteins, in Coligan J, Kruisbeek A, Margulies D, Shevach E, Strober W (eds): Current Protocols in Immunology. New York, NY. Wiley, 1991, p 8.12.1.

D’Andrea D, Lodish HF, Wong GG: Expression cloning of the murine erythropoietin receptor. Cell 57:277, 1989.

Theil S, Behrmann I, Dittrich E, Muys L, Tavernier J, Wijdenes J, Heinrich PC, Graeve L: Internalization of the interleukin 6 signal transducer gp130 does not require activation of the Jak/STAT pathway. Biochem J 330:47, 1998.

Beslu N, LaRose J, Casteran N, Birnbaum D, Lecocq E, Dubreuil P, Rottapel R: Phosphatidylinositol 3’-kinase is not required for mitogenesis or internalization of the Flt3/Flk2 receptor tyrosine kinase. J. Biol Chem. 171:20075, 1996.

Hunter MG, Avalos BR: Phosphatidylinositol 3’-kinase and SH2-containing inositol phosphatase (SHIP) are recruited by distinct positive and negative growth-regulatory domains in the granulocyte colony-stimulating factor receptor. J Immunol 1640:4979, 1998.

Joly M, Kazlauskas A, Fay FS, Covera S: Disruption of PDGF receptor trafficing by mutation of its PI-3 kinase binding sites. Science 263:684, 1994.

Carlberg K, Tapley P, Haystead C, Rohrschneider L: The role of kinase activity and the kinase insert region in ligand-induced internalization and degradation of the c-fms protein. EMBO J 10:877, 1991.

Arcasoy M, Degar B, Harris K, Forget B: Familial erythrocytosis associated with a short deletion in the erythropoiietin receptor gene. Blood 89:4628, 1997.

Koivisto U-M, Palvimo J, Janne O, Kontula K: A single-base substitution in the proximal Sp1 site of the human low density lipoprotein receptor promoter as a cause of heterozygous familial hypercholesterolemia. Proc Natl Acad Sci USA 91:10526, 1994.

Accili D, Frapier C, Mosthaf L, McKeon C, Elbein SC, Permutt MA, Ramos E, Lander E, Ullrich A, Taylor SI: Mutation in the insulin receptor gene that impairs transport of the receptor to the plasma membrand and causes insulin-resistant diabetes. EMBO J 8:2509, 1989.

Duquesnoy P, Sobrier ML, Duriez B, Dastot F, Buchanan CR, Savage MO, Preece MA, Craescu CT, Blouquit Y, Goossens M: A single amino acid substitution in the exoplasmic domain of the human growth hormone (GH) receptor confers familial GH resistance (Laron syndrome) with positive GH-binding activity by abolishing receptor homodimerization. EMBO J 13:1386, 1994.

Hermans MHA, Ward AC, Antonissen C, Karis A, Lowenberg B, Touw IP: Perturbed granulopoiesis in mice with a targeted mutation in the granulocyte colony-stimulating factor receptor gene associated with severe chronic neutropenia. Blood 92:32, 1998.

Zeidler C, Reiter A, Yakisan E, Koci B, Riehm H, Welte K. Langzeibehandlung mit rekombinantem humanen Granulozyten-Kolonien stimulierenden Faktor bei Patienten mit schwerer kongenitaler Neutropenie. Klin-Padiatr. 1993: 205:264-271.

Colton T. Longitudinal studies and the use of the life table. In: Statistics in Medicine. Boston: Little, Brown & Company: 1974:237.

Cox DR. Regression models and life tables. J Royal Stat Soc. 1972: 34B:187.

Lee, M, Fukunaga R, Lee T, Lottsfeldt J, & Nagata S. (1991) Bone modulation in sustained hematopoietic stimulation in mice. Blood 77. 2135-2141.

Real Life Stories

Letter from Brian Gamley

It has been more than 20 years since I last wrote about my Neutropenia, and what a ride it has been. Since then things have changed dramatically, some of it was not great, some not bad, and other times OK...

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