1 Stock JB, Ninfa AJ & Stock AM (1989) Protein phosphorylation and
regulation of adaptive responses in bacteria. Microbiol Rev 53, 450–
490.
2 Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell
103, 211–225.
3 Berger SL (2007) The complex language of chromatin regulation during
transcription. Nature 447, 407–412.
4 Feige MJ & Hendershot LM (2011) Disulfide bonds in ER protein folding
and homeostasis. Curr Opin Cell Biol 23, 167–175.
5 Ciechanover A, Finley D & Varshavsky A (1984) Ubiquitin dependence
of selective protein degradation demonstrated in the mammalian cell
cycle mutant ts85. Cell 37, 57–66.
6 Nath D & Shadan S (2009) The ubiquitin system. Nature 458, 421.
7 Dwek RA, Butters TD, Platt FM & Zitzmann N (2002) Targeting
glycosylation as a therapeutic approach. Nat Rev Drug Discov 1, 65–
75.
8 Simizu S, Ishida K, Wierzba MK & Osada H (2004) Secretion of
Heparanase Protein Is Regulated by Glycosylation in Human Tumor
Cell Lines. J Biol Chem 279, 2697–2703.
9 Helenius A & Aebi M (2004) Roles of N-linked glycans in the
102
endoplasmic reticulum. Annu Rev Biochem 73, 1019–1049.
10 Rek A, Krenn E & Kungl AJ (2009) Therapeutically targeting proteinglycan interactions. Br J Pharmacol 157, 686–694.
11 Moremen KW, Tiemeyer M & Nairn A V. (2012) Vertebrate protein
glycosylation: Diversity, synthesis and function. Nat Rev Mol Cell Biol
13, 448–462.
12 Sricholpech M, Perdivara I, Nagaoka H, Yokoyama M, Tomer KB &
Yamauchi M (2011) Lysyl hydroxylase 3 glucosylates
galactosylhydroxylysine residues in type I collagen in osteoblast
culture. J Biol Chem 286, 8846–8856.
13 Shcherbakova A, Tiemann B, Buettner FFR & Bakker H (2017) Distinct
C-mannosylation of netrin receptor thrombospondin type 1 repeats by
mammalian DPY19L1 and DPY19L3. Proc Natl Acad Sci U S A 114,
2574–2579.
14 Dricu A, Carlberg M, Wang M & Larsson O (1997) Inhibition of Nlinked glycosylation using tunicamycin causes cell death in malignant
cells: Role of down-regulation of the insulin-like growth factor 1
receptor in induction of apoptosis. Cancer Res 57, 543–548.
15 Contessa JN, Bhojani MS, Freeze HH, Rehemtulla A & Lawrence TS
(2008) Inhibition of N-linked glycosylation disrupts receptor tyrosine
kinase signaling in tumor cells. Cancer Res 68, 3803–3809.
103
16 Kato K, Jeanneau C, Tarp MA, Benet-Pagès A, Lorenz-Depiereux B,
Bennett EP, Mandel U, Strom TM & Clausen H (2006) Polypeptide
GalNAc-transferase T3 and Familial Tumoral Calcinosis: SECRETION
OF FIBROBLAST GROWTH FACTOR 23 REQUIRES OGLYCOSYLATION. J Biol Chem 281, 18370–18377.
17 Shajahan A, Supekar NT, Gleinich AS & Azadi P (2020) Deducing the
N- and O-glycosylation profile of the spike protein of novel
coronavirus SARS-CoV-2. Glycobiology 30, 981–988.
18 Kinoshita T & Inoue N (2002) Relationship Between Aplastic Anemia
and Paroxysmal Nocturnal Hemoglobinuria. Int J Hematol 2002 752
75, 117–122.
19 Yamauchi M & Sricholpech M (2012) Lysine post-translational
modifications of collagen. Essays Biochem 52, 113–133.
20 Spiro RG (1967) The structure of the disaccharide unit of the renal
glomerular basement membrane. J Biol Chem 242, 4813–4823.
21 Perdivara I, Yamauchi M & Tomer KB (2013) Molecular
characterization of collagen hydroxylysine O-glycosylation by mass
spectrometry: Current status. Aust J Chem 66, 760–769.
22 Richards AA, Stephens T, Charlton HK, Jones A, Macdonald GA, Prins
JB & Whitehead JP (2006) Adiponectin multimerization is dependent
on conserved lysines in the collagenous domain: Evidence for
104
regulation of multimerization by alterations in posttranslational
modifications. Mol Endocrinol 20, 1673–1687.
23 Takuwa A, Yoshida T, Maruno T, Kawahara K, Mochizuki M, Nishiuchi
Y, Kobayashi Y & Ohkubo T (2016) Ordered self-assembly of the
collagenous domain of adiponectin with noncovalent interactions via
glycosylated lysine residues. FEBS Lett 590, 195–201.
24 Risteli M, Ruotsalainen H, Bergmann U, Girija UV, Wallis R & Myllylä
R (2014) Lysyl hydroxylase 3 modifies lysine residues to facilitate
oligomerization of mannan-binding lectin. PLoS One 9, e113498.
25 Valtavaara M, Papponen H, Pirttilä AM, Hiltunen K, Helander H &
Myllylä R (1997) Cloning and characterization of a novel human lysyl
hydroxylase isoform highly expressed in pancreas and muscle. J Biol
Chem 272, 6831–6834.
26 Heikkinen J, Risteli M, Wang C, Latvala J, Rossi M, Valtavaara M &
Myllyla R (2000) Lysyl hydroxylase 3 is a multifunctional protein
possessing collagen glucosyltransferase activity. J Biol Chem 275,
36158–36163.
27 Kivirikko KI & Pihlajaniemi T (1998) Collagen hydroxylases and the
protein disulfide isomerase subunit of prolyl 4-hydroxylases. Adv
Enzymol Relat Areas Mol Biol 72, 325–398.
28 Shinkai H & Yonemasu K (1979) Hydroxylysine-linked glycosides of
105
human complement subcomponent C1q and of various collagens.
Biochem J 177, 847–852.
29 Kivirikko KI & Myllylä R (1982) [10] Posttranslational Enzymes in the
Biosynthesis of Collagen: Intracellular Enzymes. Methods Enzymol 82,
245–304.
30 Schegg B, Hülsmeier AJ, Rutschmann C, Maag C & Hennet T (2009)
Core Glycosylation of Collagen Is Initiated by Two β(1O )Galactosyltransferases . Mol Cell Biol 29, 943–952.
31 Scietti L, Chiapparino A, De Giorgi F, Fumagalli M, Khoriauli L,
Nergadze S, Basu S, Olieric V, Cucca L, Banushi B, Profumo A,
Giulotto E, Gissen P & Forneris F (2018) Molecular architecture of the
multifunctional collagen lysyl hydroxylase and glycosyltransferase
LH3. Nat Commun 9, 1–11.
32 Liefhebber JMP, Punt S, Spaan WJM & van Leeuwen HC (2010) The
human collagen beta(1-O)galactosyltransferase, GLT25D1, is a soluble
endoplasmic reticulum localized protein. BMC Cell Biol 11, 33.
33 Salo AM, Wang C, Sipilä L, Sormunen R, Vapola M, Kervinen P,
Ruotsalainen H, Heikkinen J & Myllylä R (2006) Lysyl hydroxylase 3
(LH3) modifies proteins in the extracellular space, a novel mechanism
for matrix remodeling. J Cell Physiol 207, 644–653.
34 Taga Y, Kusubata M, Ogawa-Goto K & Hattori S (2013) Site-specific
106
quantitative analysis of overglycosylation of collagen in osteogenesis
imperfecta using hydrazide chemistry and SILAC. J Proteome Res 12,
2225–2232.
35 Ishizawa Y, Niwa Y, Suzuki T, Kawahara R, Dohmae N & Simizu S
(2019) Identification and characterization of collagen-like
glycosylation and hydroxylation of CCN1. Glycobiology 29, 696–704.
36 Hofsteenge J, Müller DR, de Beer T, Löffler A, Richter WJ &
Vliegenthart JFG (1994) New Type of Linkage between a
Carbohydrate and a Protein: C-Glycosylation of a Specific Tryptophan
Residue in Human RNase Us. Biochemistry 33, 13524–13530.
37 Krieg J, Hartmann S, Vicentini A, Gläsner W, Hess D & Hofsteenge J
(1998) Recognition signal for C-mannosylation of Trp-7 in RNase 2
consists of sequence Trp-x-x-Trp. Mol Biol Cell 9, 301–309.
38 Niwa Y & Simizu S (2018) C-Mannosylation: Previous studies and
future research perspectives. Trends Glycosci Glycotechnol 30, E231–
E238.
39 Niwa Y, Suzuki T, Dohmae N & Simizu S (2016) Identification of
DPY19L3 as the C-mannosyltransferase of R-spondin1 in human cells.
Mol Biol Cell 27, 744–756.
40 Mizuta H, Kuga K, Suzuki T, Niwa Y, Dohmae N & Simizu S (2019)
C‑mannosylation of R‑spondin2 activates Wnt/β‑catenin signaling and
107
migration activity in human tumor cells. Int J Oncol 54, 2127–2138.
41 Fujiwara M, Kato S, Niwa Y, Suzuki T, Tsuchiya M, Sasazawa Y,
Dohmae N & Simizu S (2016) C-mannosylation of R-spondin3
regulates its secretion and activity of Wnt/β-catenin signaling in cells.
FEBS Lett 590, 2639–2649.
42 Gonzalez de Peredo A, Klein D, Macek B, Hess D, Peter-Katalinic J &
Hofsteenge J (2002) C-mannosylation and o-fucosylation of
thrombospondin type 1 repeats. Mol Cell Proteomics 1, 11–18.
43 Li Y, Cao C, Jia W, Yu L, Mo M, Wang Q, Huang Y, Lim JM, Ishihara
M, Wells L, Azadi P, Robinson H, He YW, Zhang L & Mariuzza RA
(2009) Structure of the F-spondin domain of mindin, an integrin ligand
and pattern recognition molecule. EMBO J 28, 286–297.
44 Morishita S, Suzuki T, Niwa Y, Dohmae N & Simizu S (2017) Dpy-19
like 3-mediated C-mannosylation and expression levels of RPEspondin in human tumor cell lines. Oncol Lett 14, 2537–2544.
45 Hofsteenge J, Blommers M, Hess D, Furmanek A & Miroshnichenko O
(1999) The four terminal components of the complement system are Cmannosylated on multiple tryptophan residues. J Biol Chem 274,
32786–32794.
46 Hartmann S & Hofsteenge J (2000) Properdin, the positive regulator of
complement, is highly C-mannosylated. J Biol Chem 275, 28569–
108
28574.
47 Miura K, Suzuki T, Sun H, Takada H, Ishizawa Y, Mizuta H, Dohmae N
& Simizu S (2021) Requirement for C-mannosylation to be secreted
and activated a disintegrin and metalloproteinase with thrombospondin
motifs 4 (ADAMTS4). Biochim Biophys Acta - Gen Subj 1865,
129833.
48 Wang LW, Leonhard-Melief C, Haltiwanger RS & Apte SS (2009) Posttranslational modification of thrombospondin type-1 repeats in
ADAMTS-like 1/punctin-1 by C-mannosylation of tryptophan. J Biol
Chem 284, 30004–30015.
49 Sorvillo N, Kaijen PH, Matsumoto M, Fujimura Y, van der Zwaan C,
Verbij FC, Pos W, Fijnheer R, Voorberg J & Meijer AB (2014)
Identification of N-linked glycosylation and putative O-fucosylation,
C-mannosylation sites in plasma derived ADAMTS13. J Thromb
Haemost 12, 670–679.
50 Hamming OJ, Kang L, Svensson A, Karlsen JL, Rahbek-Nielsen H,
Paludan SR, Hjorth SA, Bondensgaard K & Hartmann R (2012) Crystal
structure of interleukin-21 receptor (IL-21R) bound to IL-21 reveals
that sugar chain interacting with WSXWS motif is integral part of IL21R. J Biol Chem 287, 9454–9460.
51 Yoshimoto S, Katayama K, Suzuki T, Dohmae N & Simizu S (2021)
109
Regulation of N-glycosylation and secretion of Isthmin-1 by its Cmannosylation. Biochim Biophys Acta - Gen Subj 1865, 129840.
52 Sasazawa Y, Sato N, Suzuki T, Dohmae N & Simizu S (2015) Cmannosylation of thrombopoietin receptor (c-Mpl) regulates
thrombopoietin-dependent JAK-STAT signaling. Biochem Biophys Res
Commun 468, 262–268.
53 Otani K, Niwa Y, Suzuki T, Sato N, Sasazawa Y, Dohmae N & Simizu
S (2018) Regulation of granulocyte colony-stimulating factor receptormediated granulocytic differentiation by C-mannosylation. Biochem
Biophys Res Commun 498, 466–472.
54 Perez-Vilar J, Randell SH & Boucher RC (2004) C-mannosylation of
MUC5AC and MUC5B Cys subdomains. Glycobiology 14, 325–337.
55 Doucey MA, Hess D, Blommers MJJ & Hofsteenge J (1999)
Recombinant human interleukin-12 is the second example of a Cmannosylated protein. Glycobiology 9, 435–441.
56 Goto Y, Niwa Y, Suzuki T, Dohmae N, Umezawa K & Simizu S (2014)
C-mannosylation of human hyaluronidase 1: Possible roles for
secretion and enzymatic activity. Int J Oncol 45, 344–350.
57 Okamoto S, Murano T, Suzuki T, Uematsu S, Niwa Y, Sasazawa Y,
Dohmae N, Bujo H & Simizu S (2017) Regulation of secretion and
enzymatic activity of lipoprotein lipase by C-mannosylation. Biochem
110
Biophys Res Commun 486, 558–563.
58 Pronker MF, Lemstra S, Snijder J, Heck AJR, Thies-Weesie DME,
Pasterkamp RJ & Janssen BJC (2016) Structural basis of myelinassociated glycoprotein adhesion and signalling. Nat Commun 7,
13584.
59 Osada Y, Suzuki T, Mizuta H, Mori K, Miura K, Dohmae N & Simizu S
(2020) The fibrinogen C-terminal domain is seldom C-mannosylated
but its C-mannosylation is important for the secretion of microfibrilassociated glycoprotein 4. Biochim Biophys Acta - Gen Subj 1864.
60 Hendee K, Wang LW, Reis LM, Rice GM, Apte SS & Semina E V.
(2017) Identification and functional analysis of an ADAMTSL1 variant
associated with a complex phenotype including congenital glaucoma,
craniofacial, and other systemic features in a three-generation human
pedigree. Hum Mutat 38, 1485–1490.
61 Maeda Y & Kinoshita T (2008) Dolichol-phosphate mannose synthase:
Structure, function and regulation. Biochim Biophys Acta - Gen Subj
1780, 861–868.
62 Buettner FFR, Ashikov A, Tiemann B, Lehle L & Bakker H (2013) C.
elegans DPY-19 Is a C-Mannosyltransferase Glycosylating
Thrombospondin Repeats. Mol Cell 50, 295–302.
63 Watanabe K, Takebayashi H, Bepari AK, Esumi S, Yanagawa Y &
111
Tamamaki N (2011) Dpy19l1, a multi-transmembrane protein,
regulates the radial migration of glutamatergic neurons in the
developing cerebral cortex. Development 138, 4979–4990.
64 Watanabe K, Bizen N, Sato N & Takebayashi H (2016) Endoplasmic
reticulum-localized transmembrane protein Dpy19L1 is required for
neurite outgrowth. PLoS One 11, e0167985.
65 Koscinski I, Elinati E, Fossard C, Redin C, Muller J, Velez De La Calle
J, Schmitt F, Ben Khelifa M, Ray P, Kilani Z, Barratt CLR & Viville S
(2011) DPY19L2 deletion as a major cause of globozoospermia. Am J
Hum Genet 88, 344–350.
66 Niwa Y, Nakano Y, Suzuki T, Yamagishi M, Otani K, Dohmae N &
Simizu S (2018) Topological analysis of DPY19L3, a human Cmannosyltransferase. FEBS J 285, 1162–1174.
67 Yamamoto T, Gotoh M, Sasaki H, Terada M, Kitajima M & Hirohashi S
(1993) Molecular cloning and initial characterization of a novel
fibrinogen- related gene, HFREP-1. Biochem Biophys Res Commun
193, 681–687.
68 Marx G, Ben-Moshe M, Magdassi S & Gorodetsky R (2004) Fibrinogen
C-terminal peptidic sequences (Haptides) modulate fibrin
polymerization. Thromb Haemost 91, 43–51.
69 Yu HT, Yu M, Li CY, Zhan YQ, Xu WX, Li YH, Li W, Wang ZD, Ge
112
CH & Yang XM (2009) Specific expression and regulation of
hepassocin in the liver and down-regulation of the correlation of
HNF1α with decreased levels of hepassocin in human hepatocellular
carcinoma. J Biol Chem 284, 13335–13347.
70 Liu Z & Ukomadu C (2008) Fibrinogen-like protein 1, a hepatocyte
derived protein is an acute phase reactant. Biochem Biophys Res
Commun 365, 729–734.
71 Gao M, Zhan YQ, Yu M, Ge CH, Li CY, Zhang JH, Wang XH, Ge ZQ &
Yang XM (2014) Hepassocin activates the EGFR/ERK cascade and
induces proliferation of L02 cells through the Src-dependent pathway.
Cell Signal 26, 2161–2166.
72 Li CY, Cao CZ, Xu WX, Cao MM, Yang F, Dong L, Yu M, Zhan YQ,
Gao YB, Li W, Wang ZD, Ge CH, Wang QM, Peng RY & Yang XM
(2010) Recombinant human hepassocin stimulates proliferation of
hepatocytes in vivo and improves survival in rats with fulminant
hepatic failure. Gut 59, 817–826.
73 Nayeb-Hashemi H, Desai A, Demchev V, Bronson RT, Hornick JL,
Cohen DE & Ukomadu C (2015) Targeted disruption of fibrinogen like
protein-1 accelerates hepatocellular carcinoma development. Biochem
Biophys Res Commun 465, 167–173.
74 Cao MM, Xu WX, Li CY, Cao CZ, Wang ZD, Yao JW, Yu M, Zhan YQ,
113
Wang XH, Tang LJ, Chen H, Li W, Ge CH & Yang XM (2011)
Hepassocin regulates cell proliferation of the human hepatic cells L02
and hepatocarcinoma cells through different mechanisms. J Cell
Biochem 112, 2882–2890.
75 Wu HT, Ou HY, Hung HC, Su YC, Lu FH, Wu JS, Yang YC, Wu CL &
Chang CJ (2016) A novel hepatokine, HFREP1, plays a crucial role in
the development of insulin resistance and type 2 diabetes.
Diabetologia 59, 1732–1742.
76 Wang J, Sanmamed MF, Datar I, Su TT, Ji L, Sun J, Chen L, Chen Y,
Zhu G, Yin W, Zheng L, Zhou T, Badri T, Yao S, Zhu S, Boto A,
Sznol M, Melero I, Vignali DAA, Schalper K & Chen L (2019)
Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of
LAG-3. Cell 176, 334-347.e12.
77 Kimura K, Koizumi T, Urasawa T, Ohta Y, Takakura D & Kawasaki N
(2021) Glycoproteomic analysis of the changes in protein Nglycosylation during neuronal differentiation in human-induced
pluripotent stem cells and derived neuronal cells. Sci Reports 2021 111
11, 1–12.
78 Ogawa M, Mizofuchi H, Kobayashi Y, Tsuzuki G, Yamamoto M, Wada
S & Kamemura K (2012) Terminal differentiation program of skeletal
myogenesis is negatively regulated by O-GlcNAc glycosylation.
114
Biochim Biophys Acta - Gen Subj 1820, 24–32.
79 Kim HB, Seo HG, Son SJ, Choi H, Kim BG, Kweon TH, Kim S, Pai J,
Shin I, Yang WH & Cho JW (2020) O-GlcNAcylation of Mef2c
regulates myoblast differentiation. Biochem Biophys Res Commun 529,
692–698.
80 Seale P & Rudnicki MA (2000) A new look at the origin, function, and
“stem-cell” status of muscle satellite cells. Dev Biol 218, 115–124.
81 Zammit PS, Golding JP, Nagata Y, Hudon V, Partridge TA &
Beauchamp JR (2004) Muscle satellite cells adopt divergent fates: A
mechanism for self-renewal? J Cell Biol 166, 347–357.
82 Zammit PS, Partridge TA & Yablonka-Reuveni Z (2006) The skeletal
muscle satellite cell: The stem cell that came in from the cold. J
Histochem Cytochem 54, 1177–1191.
83 Weintraub H, Tapscott SJ, Davis RL, Thayer MJ, Adam MA, Lassar AB
& Miller AD (1989) Activation of muscle-specific genes in pigment,
nerve, fat, liver, and fibroblast cell lines by forced expression of
MyoD. Proc Natl Acad Sci U S A 86, 5434–5438.
84 Molkentin JD & Olson EN (1996) Combinatorial control of muscle
development by basic helix-loop-helix and MADS-box transcription
factors. Proc Natl Acad Sci U S A 93, 9366–9373.
85 Richardson BE, Nowak SJ & Baylies MK (2008) Myoblast fusion in fly
115
and vertebrates: New genes, new processes and new perspectives.
Traffic 9, 1050–1059.
86 Yoon MS (2017) mTOR as a key regulator in maintaining skeletal
muscle mass. Front Physiol 8, 788.
87 Kulik G, Klippel A & Weber MJ (1997) Antiapoptotic signalling by the
insulin-like growth factor I receptor, phosphatidylinositol 3-kinase,
and Akt. Mol Cell Biol 17, 1595–1606.
88 Delcommenne M, Tan C, Gray V, Rue L, Woodgett J & Dedhar S (1998)
Phosphoinositide-3-OH kinase-dependent regulation of glycogen
synthase kinase 3 and protein kinase B/AKT by the integrin-linked
kinase. Proc Natl Acad Sci U S A 95, 11211–11216.
89 I KY, Huang YS, Hu CH, Tseng WY, Cheng CH, Stacey M, Gordon S,
Chang GW & Lin HH (2017) Activation of adhesion GPCR
EMR2/ADGRE2 induces macrophage differentiation and inflammatory
responses via Gα16/Akt/MAPK/NF-κB signaling pathways. Front
Immunol 8, 373.
90 Bhaskar PT & Hay N (2007) The Two TORCs and Akt. Dev Cell 12,
487–502.
91 Dunlop EA & Tee AR (2009) Mammalian target of rapamycin complex
1: Signalling inputs, substrates and feedback mechanisms. Cell Signal
21, 827–835.
116
92 Saxton RA & Sabatini DM (2017) mTOR Signaling in Growth,
Metabolism, and Disease. Cell 168, 960–976.
93 Bentzinger CF, Romanino K, Cloëtta D, Lin S, Mascarenhas JB, Oliveri
F, Xia J, Casanova E, Costa CF, Brink M, Zorzato F, Hall MN &
Rüegg MA (2008) Skeletal Muscle-Specific Ablation of raptor, but Not
of rictor, Causes Metabolic Changes and Results in Muscle Dystrophy.
Cell Metab 8, 411–424.
94 Trendelenburg AU, Meyer A, Rohner D, Boyle J, Hatakeyama S &
Glass DJ (2009) Myostatin reduces Akt/TORC1/p70S6K signaling,
inhibiting myoblast differentiation and myotube size. Am J Physiol Cell Physiol 296, 1258–1270.
95 Akinleye A, Furqan M, Mukhi N, Ravella P & Liu D (2013) MEK and
the inhibitors: From bench to bedside. J Hematol Oncol 6, 27.
96 Nagata Y, Honda Y & Matsuda R (2010) FGF2 induces ERK
phosphorylation through Grb2 and PKC during quiescent myogenic
cell activation. Cell Struct Funct 35, 63–71.
97 Nagata Y, Ohashi K, Wada E, Yuasa Y, Shiozuka M, Nonomura Y &
Matsuda R (2014) Sphingosine-1-phosphate mediates epidermal
growth factor-induced muscle satellite cell activation. Exp Cell Res
326, 112–124.
98 Yaffe D & Saxel O (1977) Serial passaging and differentiation of
117
myogenic cells isolated from dystrophic mouse muscle. Nature 270,
725–727.
99 Ohno Y, Oyama A, Kaneko H, Egawa T, Yokoyama S, Sugiura T, Ohira
Y, Yoshioka T & Goto K (2018) Lactate increases myotube diameter
via activation of MEK/ERK pathway in C2C12 cells. Acta Physiol 223,
e13042.
100 Brun C, Monestier O, Legardinier S, Maftah A & Blanquet V (2012)
Murine GASP-1 N-glycosylation is not essential for its activity on
C2C12 myogenic cells but alters its secretion. Cell Physiol Biochem
30, 791–804.
101 Kitakaze T, Sakamoto T, Kitano T, Inoue N, Sugihara F, Harada N &
Yamaji R (2016) The collagen derived dipeptide hydroxyprolylglycine promotes C2C12 myoblast differentiation and myotube
hypertrophy. Biochem Biophys Res Commun 478, 1292–1297.
102 Katagiri T, Yamaguchi A, Komaki M, Abe E, Takahashi N, Ikeda T,
Rosen V, Wozney JM, Fujisawa-Sehara A & Suda T (1994) Bone
morphogenetic protein-2 converts the differentiation pathway of
C2C12 myoblasts into the osteoblast lineage. J Cell Biol 127, 1755–
1766.
103 Lin FH, Wang A, Dai W, Chen S, Ding Y & Sun L V. (2020) Lmod3
promotes myoblast differentiation and proliferation via the AKT and
118
ERK pathways. Exp Cell Res 396, 112297.
104 Miura K, Matsuki W, Ogura A, Takao K ichi & Simizu S (2020)
Identification of vibsanin A analog as a novel HSP90 inhibitor.
Bioorganic Med Chem 28, 115253.
105 Tsuchiya M, Niwa Y & Simizu S (2016) N-glycosylation of Rspondin1 at Asn137 negatively regulates its secretion and Wnt/βcatenin signaling-enhancing activity. Oncol Lett 11, 3279–3286.
106 Kawahara R, Niwa Y & Simizu S (2018) Integrin β1 is an essential
factor in vasculogenic mimicry of human cancer cells. Cancer Sci 109,
2490–2496.
107 Hayashi S, Osada Y, Miura K & Simizu S (2020) Cell-dependent
regulation of vasculogenic mimicry by carcinoembryonic antigen cell
adhesion molecule 1 (CEACAM1). Biochem Biophys Reports 21,
100734.
108 Simizu S, Suzuki T, Muroi M, Ngit SL, Takagi S, Dohmae N & Osada
H (2007) Involvement of disulfide bond formation in the activation of
heparanase. Cancer Res 67, 7841–7849.
109 Tamura Y, Simizu S, Muroi M, Takagi S, Kawatani M, Watanabe N &
Osada H (2009) Polo-like kinase 1 phosphorylates and regulates BclxL during pironetin-induced apoptosis. Oncogene 28, 107–116.
110 Simizu S, Teruya T, Nogawa T, Aono H, Ueki M, Uramoto M,
119
Kobayashi Y & Osada H (2009) Deamino-hydroxy-phoslactomycin B,
a biosynthetic precursor of phoslactomycin, induces myeloid
differentiation in HL-60 cells. Biochem Biophys Res Commun 383,
406–410.
111 Katsuyama S, Sugino K, Sasazawa Y, Nakano Y, Aono H, Morishita
K, Kawatani M, Umezawa K, Osada H & Simizu S (2016)
Identification of a novel compound that inhibits osteoclastogenesis by
suppressing nucleoside transporters. FEBS Lett 590, 1152–1162.
112 Sunadome K, Yamamoto T, Ebisuya M, Kondoh K, Sehara-Fujisawa A
& Nishida E (2011) ERK5 Regulates Muscle Cell Fusion through Klf
Transcription Factors. Dev Cell 20, 192–205.
113 Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R,
Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H,
Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S,
Yamamoto J ichi, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari
K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A,
Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M,
Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe
K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M,
Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K,
Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono
120
Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori
K, Takahashi-Fujii A, Hara H, Tanase T o., Nomura Y, Togiya S,
Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki
H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H,
Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N,
Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi
H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama
A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A,
Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H,
Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao
M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y,
Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K,
Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki
M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T,
Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K,
Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita
R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T & Sugano S
(2003) Complete sequencing and characterization of 21,243 full-length
human cDNAs. Nat Genet 2004 361 36, 40–45.
114 Reid KBM (1979) Complete amino acid sequences of the three
collagen-like regions present in subcomponent C1q of the first
121
component of human complement. Biochem J 179, 367–371.
115 Taniguchi T, Woodward AM, Magnelli P, McColgan NM, Lehoux S,
Jacobo SMP, Mauris J & Argüeso P (2017) N-Glycosylation affects the
stability and barrier function of the MUC16 mucin. J Biol Chem 292,
11079–11090.
116 Frank M, Beccati D, Leeflang BR & Vliegenthart JFG (2020) CMannosylation Enhances the Structural Stability of Human RNase 2.
iScience 23, 101371.
117 Ono Y, Gnocchi VF, Zammit PS & Nagatomi R (2009) Presenilin-1
acts via Id1 to regulate the function of muscle satellite cells in a γsecretase-independent manner. J Cell Sci 122, 4427–4438.
118 Lacour F, Vezin E, Bentzinger CF, Sincennes MC, Giordani L, Ferry
A, Mitchell R, Patel K, Rudnicki MA, Chaboissier MC, Chassot AA &
Le Grand F (2017) R-spondin1 Controls Muscle Cell Fusion through
Dual Regulation of Antagonistic Wnt Signaling Pathways. Cell Rep 18,
2320–2330.
122
附録
Table S-1 Cell numbers to calculate fusion index.
Parent
DPY19L3-KO
Nuclei in polynuclear cells
149
69
140
15
14
All Nuclei
406
201
294
97
169
171
123
謝辞
本研究は、著者が慶應義塾大学大学院 生物化学研究室在籍時に、同理工学
部 清水史郎教授のご指導のもと行いました。研究遂行にあたり、実験結果や論
文の内容について日常的にディスカッションを重ねてくださったお陰です。ここ
に厚く御礼申し上げます。
本論文の執筆にあたり、慶應義塾大学理工学部 末永聖武教授、宮本憲二教
授、松本緑准教授に数多くの貴重なご意見をいただきました。心より感謝申し上
げます。
タンパク質の糖鎖修飾の検出にあたり、質量分析を行ってくださった、国
立研究開発法人 理化学研究所 環境科学研究センター 生命分子解析ユニットの
堂前直博士、鈴木健裕博士に、心より御礼申し上げます。
本研究の遂行にあたり、的確なご指導、ご鞭撻、ご助言を賜りました、東
京工業大学 化学生命科学研究所 三浦一輝博士に深く感謝いたします。
常日頃から実験についてご指摘やアドバイスをしてくださった、生物化学
研究室の先輩方、同期、後輩に心から感謝いたします。皆様が作り上げた研究室
の温かい雰囲気に支えられて、ここまで研究を続けることができました。
最後に、毎日の研究室生活を支えてくれた家族に、深く感謝いたします。
...