Faculty Profiles - KINOSHITA, Makoto

Papers - KINOSHITA, Makoto

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Phosphorylation of adult type Sept5 (CDCrel-1) by cyclin-dependent kinase 5 inhibits interaction with syntaxin-1 Reviewed Open Access

Makoto Taniguchi, Masato Taoka, Makoto Itakura, Akiko Asada, Taro Saito, Makoto Kinoshita, Masami Takahashi, Toshiaki Isobe, Shin-ichi Hisanaga

Journal of Biological Chemistry Vol. 282 ( 11 ) page： 7869 - 7876 2007.3

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Increasing evidence implicates cyclin-dependent kinase 5 (Cdk5) in neuronal synaptic function. We searched for Cdk5 substrates in synaptosomal fractions prepared from mouse brains. Mass spectrometric analysis after two-dimensional SDS-PAGE identified several synaptic proteins phosphorylated by Cdk5-p35; one protein identified was Sept5 (CDCrel-1). Although septins were isolated originally as cell division-related proteins in yeast, Sept5 is expressed predominantly in neurons and is implicated in exocytosis. We confirmed that Sept5 is phosphorylated by Cdk5p35 in vitro and identified Ser(17) of adult type Sept5 (Sept5_v1) as a major phosphorylation site. We found that Ser17 of Sept5_v1 is phosphorylated in mouse brains. Coimmunoprecipitation from synaptosomal fractions and glutathione S-transferase-syntaxin-1A pulldown assays of Sept5_v1 expressed in COS-7 cells showed that phosphorylation of Sept5_v1 by Cdk5-p35 decreases the binding to syntaxin-1. These results indicate that the interaction of Sept5 with syntaxin-1 is regulated by the phosphorylation of Sept_v1 at Ser(17) by Cdk5-p35.

DOI： 10.1074/jbc.M609457200

Sept4, a Component of Presynaptic Scaffold and Lewy Bodies, Is Required for the Suppression of α-Synuclein Neurotoxicity Reviewed Open Access

Masafumi Ihara, Nobuyuki Yamasaki, Akari Hagiwara, Ai Tanigaki, Ayumi Kitano, Rie Hikawa, Hidekazu Tomimoto, Makoto Noda, Masashi Takanashi, Hideo Mori, Nobutaka Hattori, Tsuyoshi Miyakawa, Makoto Kinoshita

Neuron Vol. 53 ( 4 ) page： 519 - 533 2007.2

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

In Parkinson disease (PID), alpha-synuclein aggregates called Lewy bodies often involve and sequester Septin4 (Sept4), a polymerizing scaffold protein. However, the pathophysiological significance of this phenomenon is unclear. Here, we show the physiological association of Sept4 with alpha-synuclein, the dopamine transporter, and other presynaptic proteins in dopaminergic neurons; mice lacking Sept4 exhibit diminished dopaminergic neurotransmission due to scarcity of these presynaptic proteins. These data demonstrate an important role for septin scaffolds in the brain. In transgenic mice that express human alpha-synuclein(A53T) (a mutant protein responsible for familial PD), loss of Sept4 significantly enhances neuropathology and locomotor deterioration. In this PID model, insoluble deposits of Ser(129)-phosphorylated alpha-synuclein(A53T) are negatively correlated with the dosage of Sept4. In vitro, direct association with Sept4 protects alpha-synuclein against self-aggregation and Ser(129) phosphorylation. Taken together, these data show that Sept4 may be involved in PID as a dual susceptibility factor, as its insufficiency can diminish dopaminergic neurotransmission and enhance alpha-synuclein neurotoxicity.

DOI： 10.1016/j.neuron.2007.01.019

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蛍光偏光顕微鏡が解いたセプチン線維配向の謎 Invited Reviewed

木下　専

蛋白質核酸酵素 Vol. 52 ( 1 ) 2007.1

Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen Invited

Kinoshita, M., Watanabe, N.

Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme Vol. 52 ( 13 Suppl ) page： 1796 - 1799 2007

表現型スクリーニングで同定された紡錘体双極性の阻害剤 Invited

木下　専、渡邊直樹

蛋白質核酸酵素　融合発展する構造生物学とケミカルバイオロジーの最前線 Vol. 53 ( 13 ) page： 1796 - 1799 2007

細胞分裂と細胞形態形成におけるGTP結合蛋白質セプチンの役割 Invited

木下　専

生化学(日本生化学会誌) Vol. 78 ( 8 ) page： 755 - 759 2006.8

Diversity of septin scaffolds Invited Reviewed

Makoto Kinoshita

Current Opinion in Cell Biology Vol. 18 ( 1 ) page： 54 - 60 2006.2

Authorship：Lead author,　Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

Septins are ubiquitous GTP-binding proteins generally regarded as cytoskeletal components. Higher-order septin assemblies represented by the yeast septin collar function as cytoskeleton, providing structural support and scaffolds for many cellular factors. In metazoans, however, typical higher-order septin assemblies are often less predominant than dispersed 'low-order' septin populations. Recent studies revealed that septin populations with no obvious structure that had previously escaped our attention serve as scaffolds for kinetochore motor proteins and as sequestering depots for microtubule regulators. Unlike classic cytoskeletal polymers, which form uniform, continuous networks, septin polymers, being diverse, discontinuous and relatively static, seem suited to form discrete scaffolds. Thus, the septin system might be redefined as discrete scaffolds that are conditionally united to behave like cytoskeleton.

DOI： 10.1016/j.ceb.2005.12.005

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再構成系と遺伝子破壊マウスによるセプチン系の解析 Invited

木下　専

細胞工学 Vol. 25 ( 7 ) page： 785 - 789 2006

Disruption of Sept6, a fusion partner gene of MLL, does not affect ontogeny, leukemogenesis induced by MLL-SEPT6, or phenotype induced by the loss of Sept4 Reviewed Open Access

R Ono, M Ihara, H Nakajima, K Ozaki, Y Kataoka-Fujiwara, T Taki, K Nagata, M Inagaki, N Yoshida, T Kitamura, Y Hayashi, M Kinoshita, T Nosaka

Molecular and Cellular Biology Vol. 25 ( 24 ) page： 10965 - 10978 2005.12

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC MICROBIOLOGY

Septins are evolutionarily conserved GTP-binding proteins that can heteropolymerize into filaments. Recent studies have revealed that septins are involved in not only diverse normal cellular processes but also the pathogenesis of various diseases, including cancer. SEPT6 is ubiquitously expressed in tissues and one of the fusion partner genes of MLL in the 11q23 translocations implicated in acute leukemia. However, the roles of this septin in vivo remain elusive. We have developed Sept6-deficient mice that exhibited neither gross abnormalities, changes in cytokinesis, nor spontaneous malignancy. Sept6 deficiency did not cause any quantitative changes in any of the septins evaluated in this study, nor did it cause any additional changes in the Sept4-deficient mice. Even the depletion of Sept11, a close homolog of Sept6, did not affect the Sept6-null cells in vitro, thus implying a high degree of redundancy in the septin system. Furthermore, a loss of Sept6 did not alter the phenotype of myeloproliferative disease induced by MLL-SEPT6, thus suggesting that Sept6 does not function as a tumor suppressor. To our knowledge, this is the first report demonstrating that a disruption of the translocation partner gene of MLL in 11q23 translocation does not contribute to leukemogenesis by the MLL fusion gene.

DOI： 10.1128/MCB.25.24.10965-10978.2005

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セプチン系細胞骨格と精子無力症 Invited

西山博之、木下　専

医学のあゆみ Vol. 214 ( 3 ) page： 221 - 222 2005.7

A mitotic septin scaffold required for mammalian chromosome congression and segregation Reviewed International coauthorship International journal Open Access

Vol. 307 page： 1781 - 1785 2005.3

Cortical Organization by the Septin Cytoskeleton Is Essential for Structural and Mechanical Integrity of Mammalian Spermatozoa Reviewed Open Access

Masafumi Ihara, Ayae Kinoshita, Shuichi Yamada, Hiromitsu Tanaka, Ai Tanigaki, Ayumi Kitano, Motohito Goto, Kazutoshi Okubo, Hiroyuki Nishiyama, Osamu Ogawa, Chiaki Takahashi, Shigeyoshi Itohara, Yoshitake Nishimune, Makoto Noda, Makoto Kinoshita

Developmental Cell Vol. 8 ( 3 ) page： 343 - 352 2005.3

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

Septins are polymerizing GTP binding proteins required for cortical organization during cytokinesis and other cellular processes. A mammalian septin gene Sept4 is expressed mainly in postmitotic neural cells and postmeiotic male germ cells. In mouse and human spermatozoa, SEPT4 and other septins are found in the annulus, a cortical ring which separates the middle and principal pieces. Sept4(-/-) male mice are sterile due to defective morphology and motility of the sperm flagellum. In Sept4 null spermatozoa, the annulus is replaced by a fragile segment lacking cortical material, beneath which kinesin-mediated intraflagellar transport stalls. The sterility is rescued by injection of sperm into oocytes, demonstrating that each Sept4 null spermatozoon carries an intact haploid genome. The annulus/septin ring is also disorganized in spermatozoa from a subset of human patients with asthenospermia syndrome. Thus, cortical organization based on circular assembly of the septin cytoskeleton is essential for the structural and mechanical integrity of mammalian spermatozoa.

DOI： 10.1016/j.devcel.2004.12.005

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Septins and Cytokinesis Invited Reviewed International coauthorship

Encyclopedia of Biological Chemistry Vol. 4 page： 22 - 26 2004.11

Endomucin, a sialomucin expressed in high endothelial venules, supports L-selectin-mediated rolling Reviewed Open Access

H Kanda, T Tanaka, M Matsumoto, E Umemoto, Y Ebisuno, M Kinoshita, M Noda, R Kannagi, T Hirata, T Murai, M Fukuda, M Miyasaka

International Immunology Vol. 16 ( 9 ) page： 1265 - 1274 2004.9

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Lymphocyte homing to lymph nodes is regulated by transient but specific interactions between lymphocytes and high endothelial venules (HEVs), the initial phase of which is mainly governed by the leukocyte adhesion molecule L-selectin, which recognizes sulfated and sialylated O-linked oligosaccharides displayed on sialomucin core proteins. One of the sialomucin proteins, endomucin, is predominantly expressed in vascular endothelial cells of a variety of tissues including the HEVs of lymph nodes; however, whether it functions as a ligand for L-selectin remains to be formally proven. Here we show that the endomucin splice isoform a is predominantly expressed in Ill HEVs and MAdCAM-1(+) HEVs, as seen in non-HEV-type vascular endothelial cells. Using affinity purification with soluble L-selectin, we found that HEV endomucin is specifically modified with L-selectin-reactive oligosaccharides and can bind L-selectin as well as an HEV-specific mAb, MECA-79. Our results also indicated that a 90-100 kDa endomucin species is preferentially decorated with L-selectin-reactive sugar chains, whereas an 80 kDa species represents conventional forms expressed in non-HEV-type vascular endothelial cells in lymph nodes. Furthermore, a CHO cell line expressing endomucin together with a specific combination of carbohydrate-modifying enzymes [core-2 beta-1,6-N-acetylglucosaminyltransferase (C2GnT), alpha-1,3-fucosyltransferase VII (FucTVII) and L-selectin ligand sulfotransferase (LSST)] showed L-selectin-dependent rolling under flow conditions in vitro. These results suggest that when endomucin is appropriately modified by a specific set of glycosyltransferases and a sulfotransferase, it can function as a ligand for L-selectin, and that the endomucin expressed in HEVs may represent another sialomucin ligand for L-selectin.

DOI： 10.1093/intimm/dxh128

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Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat Reviewed

H. Tomimoto, M. Ihara, H. Wakita, R. Ohtani, J. X. Lin, I. Akiguchi, M. Kinoshita, H. Shibasaki

Acta Neuropathologica Vol. 106 ( 6 ) page： 527 - 534 2003.12

Language：English Publishing type：Research paper (conference, symposium, etc.)

Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52-64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter. Using the TUNEL method, the number of cells showing DNA fragmentation increased three- to eightfold between 3 and 30 days post-surgery compared to sham-operated animals. Double labeling with TUNEL and immunohistochemistry for markers of either astroglia or oligodendroglia showed that DNA fragmentation occurred in both of these glia. Messenger RNA for caspase-3 increased approximately twofold versus the sham-operated rats between 1 and 30 days post-surgery. Immunohistochemistry revealed up-regulation of caspase-3 in the oligodendroglia of the white matter, and also in the astroglia and neurons of the gray matter. Molecules involved in apoptotic signaling such as TNF-α and Bax were also up-regulated in glial cells. These results indicate that chronic cerebral hypoperfusion induces white matter degeneration in association with DNA fragmentation in oligodendroglia.

DOI： 10.1007/s00401-003-0749-3

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The Septins (Protein Family Review) Invited Reviewed Open Access

Makoto Kinoshita

Genome Biology Vol. 4 ( 236 ) page： 1 - 9 2003.10

Authorship：Lead author,　Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：11

The septins make up a family of guanine-nucleotide binding proteins, most of which polymerize to form filaments. Septin genes have been found in fungi and animals but not in protozoa or plants
yeasts have seven septin genes and humans have twelve, but Caenorhabditis elegans has only two. Some septin genes generate multiple polypeptides by alternative splicing or alternative translation start sites. Of the five conserved motifs found in other members of the GTPase superfamily, three are highly conserved in septins. Septin filaments are thought to form a cytoskeletal system that organizes higher-order structures by self-assembly and templated assembly. These multifunctional proteins are best known for their role in cytokinesis, but other functions in dividing and non-dividing cells have evolved in different lineages: budding yeast has septins specific for sporulation
nematode septins are implicated in postembryonic morphogenesis of multiple cell lineages
fly septins are associated with the development of germ cells, photoreceptor cells and nervous system
and mammalian septins are implicated in exocytosis, tumorigenesis, apoptosis, synaptogenesis and neurodegeneration.

DOI： 10.1186/gb-2003-4-11-236

Open Access

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PubMed

Assembly of mammalian septins Invited

Makoto Kinoshita

Journal of Biochemistry Vol. 134 ( 4 ) page： 491 - 496 2003.10

Authorship：Lead author,　Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：JAPANESE BIOCHEMICAL SOC

Septins are a conserved family of polymerizing guanine nucleotide binding proteins associated with diverse processes in dividing and non-dividing cells. In humans, 12 septin genes generate dozens of polypeptides, many of which comprise heterooligomeric complexes. Native and recombinant mammalian septin complexes are purified as similar to8-nm-thick filaments of variable length. Ultrastructurally, a mammalian septin filament appears an irregular array of structural segments, whose polarity is obscure. The filaments have a potential to self-assemble into higher-order structures by lateral stacking and tandem annealing, eventually forming uniformly curved bundles, i.e., rings and coils. The septin filaments also undergo templated assembly along existing actin bundles containing an adapter protein, anillin. The resultant higher-order assembly of septin filaments may provide scaffolds to recruit other molecules and/or help organize the actin-based structures. The in vitro self-assembly is an irreversible process, which is not coupled with robust nucleotide exchange or hydrolysis. In contrast, septin-based structures rearrange and disassemble in cells, which might be controlled by diverse factors (e.g., the Cdc42-borg system, anillin, syntaxin, phospholipids) and covalent modifications (e.g., phosphorylation, ubiquitination, sumoylation). An immediate goal of septin biochemistry is to define the mechanisms of assembly and disassembly of this elusive cytoskeleton.

DOI： 10.1093/jb/mvg182

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Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies Reviewed Open Access

M Ihara, H Tomimoto, H Kitayama, Y Morioka, Akiguchi, I, H Shibasaki, M Noda, M Kinoshita

Journal of Biological Chemistry Vol. 278 ( 26 ) page： 24095 - 24102 2003.6

Authorship：Last author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

alpha-Synuclein-positive cytoplasmic inclusions are a pathological hallmark of several neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Here we report that Sept4, a member of the septin protein family, is consistently found in these inclusions, whereas five other septins (Sept2, Sept5, Sept6, Sept7, and Sept8) are not found in these inclusions. Sept4 and alpha-synuclein can also be co-immunoprecipitated from normal human brain lysates. When co-expressed in cultured cells, FLAG-tagged Sept4 and Myc-tagged alpha-synuclein formed detergent-insoluble complex, and upon treatment with a proteasome inhibitor, they formed Lewy body-like cytoplasmic inclusions. The tagged Sept4 and alpha-synuclein synergistically accelerated cell death induced by the proteasome inhibitor, and this effect was further enhanced by expression of another Lewy body-associated protein, synphilin-1, tagged with the V5 epitope. Moreover, co-expression of the three proteins (tagged Sept4, alpha-synuclein, and synphilin-1) was sufficient to induce cell death. These data raise the possibility that Sept4 is involved in the formation of cytoplasmic inclusions as well as induction of cell death in alpha-synuclein-associated neurodegenerative disorders.

DOI： 10.1074/jbc.M301352200

細胞生物学から「ケミカルジェネティクス」へ：ハーバード大学Mitchison研究室における研究の展開 Invited Reviewed

木下　専

現代化学 2003年2月号 page： 21 - 24 2003.1

Self- and Actin-Templated Assembly of Mammalian Septins Reviewed International coauthorship Open Access

Makoto Kinoshita, Christine M. Field, Margaret L. Coughlin, Aaron F. Straight, Timothy J. Mitchison

Developmental Cell Vol. 3 ( 6 ) page： 791 - 802 2002.12

Authorship：Lead author,　Corresponding author Language：English Publishing type：Research paper (scientific journal) Publisher：Elsevier {BV}

Septins are polymerizing GTPases required for cytokinesis and cortical organization. The principles by which they are targeted to, and assemble at, specific cell regions are unknown. We show that septins in mammalian cells switch between a linear organization along actin bundles and cytoplasmic rings, approximately 0.6 mum in diameter. A recombinant septin complex self-assembles into rings resembling those in cells. Linear organization along actin bundles was reconstituted by adding an adaptor protein, anillin. Perturbation of septin organization in cells by expression of a septin-interacting fragment of anillin or by septin depletion via siRNA causes loss of actin bundles. We conclude that septins alone self-assemble into rings, that adaptor proteins recruit septins to actin bundles, and that septins help organize these bundles.

DOI： 10.1016/s1534-5807(02)00366-0

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Papers - KINOSHITA, Makoto