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細胞膜研究室

Laboratory of Biomembrane

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Tokyo Metropolitan Institute of Medical Science Link

Physiological Functions of Glycosphingolipids in Transmembrane Signaling

Kohji Kasahara, Ph D

Introduction

Glycosphingolipids are found in the outer leaflet of the plasma membrane of all vertebrate cells and are thought to play functional roles in cellular interactions and the control of cell proliferation. In the nervous system, where gangliosides, sialic acid-containing glycosphingolipids, are particularly abundant, the species and amounts of gangliosides undergo profound changes during development, suggesting that they may play fundamental roles in this process. The addition of exogenous gangliosides to primary cultures of neurons and neuroblastoma cells in vitro stimulates cellular differentiation with concomitant neurite sprouting and extension. Glucosylceramide synthesis, the first glycosylation step of glycosphingolipid synthesis, is required for embryonic development. Transfection of the ganglioside GD3 synthase cDNA into neuroblastoma cells induces their cholinergic differentiation and neurite sprouting. GD3 synthase gene knock-out mice exhibit impairment of regeneration of the lesioned hypoglossal nerves. Finally, ganglioside-deficient mice exhibit central nervous system degeneration. These data show that gangliosides are involved in neural cell differentiation and brain development. However, the molecular mechanisms and signal transduction manners underlying the ganglioside-dependent neural functions remain obscure.

Isolation of glycosphingolipid-binding proteins

We have been investigating the association of gangliosides with specific proteins in the central nervous system to clarify the ganglioside-dependent neural functions. We previously demonstrated that anti-ganglioside GD3 antibody (R24) coimmunoprecipitates phosphorylated proteins of 40, 53, 56 and 80 kDa and proteins of the 135 kDa from rat cerebellar neurons. Of these proteins, the 53 and 56 kDa phosphoproteins were identified as the Src family kinase Lyn (Kasahara et al. J. Biol. Chem. 272 29947-29953, 1997) Link. The 135-kDa protein was identified as the glycosylphosphatidylinositol -anchored neuronal cell adhesion molecule TAG-1 (Kasahara et al. J. Biol. Chem. 275 34701-34709, 2000) Link. We have demonstrated that TAG-1 transduces a signal via Lyn in the lipid rafts of primary cerebellar granule neurons and promotes neurite outgrowth (Kasahara et al. Neurochemical Res. 27 823-829, 2002) Link. We identified the 40 kDa phosphoprotein as the α subunit of the heterotrimeric G protein, Go (Goα), and demonstrated the activation-dependent translocation of Goα to lipid rafts, leading to the growth cone collapse of cerebellar granule neurons (Yuyama et al. J.Biol.Chem., 282, 26392-26400, 2007) Link. 80kDa phosphoprotein was identified as Csk-binding protein Cbp, a substrate for Src family kinases (Sekino-Suzuki et al. J.Neurochem. 124 514-522, 2013 : article featured as an editorial highlight J.Neurochem. 124 432-435 2013) Link. Fig.1 shows isolation method of glycosphingolipid-binding proteins by coimmunoprecipitation with anti-glycosphingolipid antibody.

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Fig. 1 : Isolation of glycosphingolipid-binding proteins

Lipid rafts

Glycosphingolipids are known to exist in clusters and form microdomains containing cholesterol at the surface of the plasma membrane called lipid rafts. The glycosphingolipid microdomains have been implicated in signal transduction because a variety of signaling molecules, such as the Src family kinase, are associated with them. We found that anti-ganglioside GD3 antibody coprecipitates Lyn, Cbp, Goα and TAG-1. Sucrose density gradient analysis showed that the ganglioside GD3-binding ptoteins were detected in raft fraction, suggesting that immunoprecipitation with anti-glycosphingolipid antibody is an immunoisolation method for lipid rafts (Kasahara et al. Glycoconjugate J. 17 152-162, 2000) Link. Fig. 2 shows a hypothetical model of association of ganglioside GD3-binding proteins with lipid rafts of cerebellar granule cells.

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Fig. 2 : Association of ganglioside-binding proteins with lipid rafts

Src family tyrosine kinase Lyn

Lyn is one of non-receptor protein-tyrosine kinases of the Src subfamily. Lyn is thought to anchor onto the inner leaflet of lipid rafts via N-terminal lipid modification (palmitoylation and myristoylation). Binding of R24 to ganglioside GD3 activates Lyn and induces rapid tyrosine phosphorylation of several proteins in primary cerebellar granule neurons. This suggests functional association of Lyn with ganglioside GD3 in cell membrane.

Csk-binding protein Cbp

Cbp is a lipid raft-anchored adaptor protein, a substrate for Src family tyrosine kinases. R24 treatment of the rat primary cerebellar granule neurons induces Lyn activation and tyrosine 314 phosphorylation of Cbp. Immunoblotting analysis showed that the active form of Lyn and the Tyr314-phosphorylated form of Cbp were highly accumulated in the DRM raft fraction prepared from the developing cerebellum. Cbp has been implicated in the regulation of Src family kinase through recruitment of Csk, a negative regulator of Src family kinase, to lipid rafts. The interaction of Cbp and Csk is dependent upon the phosphorylation of Cbp Tyr-314 by Src family kinases. Subpopulation of Csk and the inhibitory C-terminal tyrosine 508 phosphorylation of Lyn were detected in the DRM raft fraction of rat developing cerebellum. Fig. 3 shows negative feedback regulation of Lyn by Cbp in lipid rafts of cerebellar granule neurons.

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Fig. 3 : Model of Lyn/Cbp signaling in lipid rafts on cerebellar granule neurons



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Fig. 4 : Activation model of Src family kinase Lyn by glycosphingolipid crosslinking

Fig. 4 shows activation model of Lyn and tyrosine phosphorylation of Cbp by glycosphingolipid crosslinking. It is assumed that glycosphingolipid crosslinking leads to coalescence of lipid rafts. This may induce clustering of Src family kinase and transphosphorylation of tyrosine residue at activation site.

GPI-anchored neuronal cell adhesion molecule TAG-1

We attempted to identify the cell-surface molecules involved in Lyn signaling, because Lyn is a nonreceptor-type kinase. We found that R24 co-immunoprecipitates TAG-1 and that the antibody-mediated crosslinking of TAG-1 induces Lyn activation (Fig. 5). Furthermore, enzymatic degradation of cell-surface ganglioside reduces TAG-mediated Lyn activation, suggesting that gangliosides are involved in TAG-1-mediated signaling in lipid rafts.

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Fig. 5 : Signal transduction of GPI-anchored protein TAG-1 in lipid rafts

Heterotrimeric G protein Goα

Using sucrose gradient assay with cerebellar membranes, Goα, but not Gβγ, was observed in detergent-resistant membrane (DRM) raft fractions, after the addition of GTPγS which stabilizes Go the active form. On the other hands, both Goα and Gβγ were excluded from DRM fractions in the presence of GDPβS which stabilizes Go in its inactive state. Furthermore, Goα was concentrated in neuronal growth cones. The treatment with stromal derived factor (SDF)-1α, a physiological ligand for G protein-coupled receptor, stimulated [35S] GTPγS binding to Goα, and caused Goα translocation to DRM fractions, leading to growth cone collapse of cerebellar granule neurons. After GTPγS treatment, Goα is co-immunoprecipitated with monoclonal antibody to GAP-43, a growth cone-enriched and raft marker protein.  These results demonstrate the involvement of signal-dependent Goα translocation to rafts in the growth cone behavior of cerebellar granule neurons (Fig. 6).

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Fig. 6 : Activation-dependent recruitment of Goα to lipid rafts

In this laboratory, glycosphingolipids have been found to function as platforms in transmembrane signaling for the attachment of various signaling molecules.

Various molecules involved in diseases such as viruses (HIV, influenza virus), bacterial toxins (verotoxin), amyloid β proteins (Alzheimer’s disease) and anti-glycosphingolipid antibodies (autoimmune disease) are known to be associated with glycosphingolipids on cellular membranes. Our final goal is to elucidate the molecular mechanisms of these glycosphingolipid-mediated diseases.

Laboratory Members

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Team Leader : Kohji Kasahara

E-mail:

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Education:

1982-1986  Faculty of Science, Tokyo Institute of Technology, BSc in chemistry
1986-1988  Graduate School of Science, Tokyo Institute of Technology
       MSc in chemistry
1988-1992  Institute of Medical Science, University of Tokyo, Ph D

Professional experience:

1992-2003  Research Scientist, Tokyo Metropolitan Institute of Medical Science
2003-2005  Independent Scientist,Tokyo Metropolitan Institute of Medical Science
2005-2010  Project Subleader, Tokyo Metropolitan Institute of Medical Science
2010-     Team Leader, Tokyo Metropolitan Institute of Medical Science

2001-2005  PRESTO, Japan Science and Technology Agency

Awards:

2001  4th Young Investigator Award, Japanese Society of Carbohydrate Research
2001  Investigator Award, Tokyo Metropolitan Government
2010  Poster Award, 33rd Congress of Japanese Society on Thrombosis and Hemostasis

Researcher

Ikuo Kawashima, Kiyoshi Ogura, Tomohiro Iguchi, Keisuke Komatsuya

Student

Michiko Fukuyama

References

(1) Kikuchi, T.,Takagi, J., Kasahara, K., Inada, Y., and Saito, Y.
Interaction between plasma factor XIII and collagen.
Thromb. Res., 43, 213-218, 1986

(2) Kasahara, K., Takagi, J., Sekiya, F., Inada, Y., and Saito, Y.
Analysis of distribution of receptors among platelets by flow cytometry.
Thromb. Res., 45, 763-770, 1987

(3) Takagi, J., Sekiya, F., Kasahara, K., Inada, Y., and Saito, Y
Venom from souther copperhead snake (Agkistrodon contortrix contortrix).
II. A unique phospholipase A2 that induces platelet aggregation.
Toxicon, 26,199-206, 1988

(4) Kasahara, K., Takagi, J., Sekiya, F., Inada, Y., and Saito, Y.
"A" subunit of factor XIII is present on bovine platelet membrane and mediates collagen-induced platelet activation.
Thromb. Res., 50, 253-263, 1988

(5) Takagi, J., Kasahara, K., Sekiya, F., Inada, Y., and Saito, Y.
Subunit B of factor XIII is present in bovine platelets.
Thromb. Res., 50, 767-774, 1988

(6) Sekiya, F., Takagi, J., Kasahara, K., Inada, Y., and Saito, Y.
Plasma albumin is essential for collagen-induced platelet aggregation.
Thromb. Res., 50, 837-846, 1988

(7) Takagi, J., Sekiya, F., Kasahara, K., Inada, Y., and Saito, Y.
Inhibition of platelet-collagen interaction by propolypeptide of von Willebrand factor.
J. Biol. Chem., 264, 6017-6020, 1989

(8) Takagi, J., Kasahara, K., Sekiya, F., Inada, Y., and Saito, Y.
A collagen-binding glycoprotein from bovine platelets is identical to propolypeptide of von Willebrand factor.
J. Biol. Chem., 264, 10425-10430, 1989

(9) Chida, K., Tsunenaga, M., Kasahara, K., Kohno, Y., and Kuroki, T.
Regulation of creatine phospholinase B activity by protein kinase C.
Biochem. Biophys. Res. Commun., 173, 346-350, 1990

(10) Chida, K., Kasahara, K., Tsunenaga, M., Kohno, Y., Yamada, S., Ohmi,
S., and Kuroki, T.
Purification and identification of creatine phosphokinase B as a substrate
of protein kinase C in mouse skin in vivo.
Biochem. Biophys. Res. Commun., 173, 351-357, 1990

(11) Kasahara,K., Chida,K., Tsunenaga,M., Kohno,Y., Ikuta,T., and Kuroki,T.
Identification of lamin B2 as a substrate of protein kinase C in BALB/MK-2 mouse keratinocytes.
J. Biol. Chem., 266, 20018-20023, 1991

(12) Kasahara, K., Ikuta, T., Chida, K., Asakura, R., and Kuroki, T.
Rapid phosphorylation of 28-kDa heat-shock protein by treatment with
okadaic acid and phorbol ester of BALB/MK-2 mouse keratinocytes.
Eur. J. Biochem., 213, 1101-1107, 1993

(13) Kasahara, K., Kartasova,T., Ren,X.-Q.,Ikuta, T., Chida, K., and Kuroki, T
Hyperphosphorylation of keratins by treatment with okadaic acid of BALB/MK-2 mouse keratinocytes.
J. Biol. Chem., 268, 23531-23537, 1993

(14) Kasahara, K., Guo, L., Nagai, Y., and Sanai, Y.
Enzymatic assay of glycosphingolipid sialyltransferase using reverse- phase
thin-layer chromatography.
Anal. Biochem. 218, 224-226, 1994

(15) Nara, K, Watanabe, Y, Maruyama, K., Kasahara, K., Nagai, Y and Sanai,Y.
Expression cloning of a CMP-NeuAc:NueAca2-3Galb1-4 Glcb1-1'Cer α2,8-sialyltransferase (GD3 synthase) from human melanoma cells.
Proc. Natl. Acad. Sci. USA, 91, 7952-7956, 1994.

(16) Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y.
Association of src family tyrosine kinase Lyn with ganglioside GD3 in rat brain.
Possible regulation of Lyn by glycosphingolipid in caveolae-like domains.
J. Biol. Chem. ,272 29947-29953, 1997

(17) Kasahara, K., Watanabe, K., Takeuchi, K., Kaneko, H., Oohira, A.,Yamamoto, T., and Sanai, Y.
Involvement of gangliosides in GPI-anchored neuronal cell adhesion molecule TAG-1 signaling in lipid rafts.
J. Biol. Chem. ,275 34701-34709, 2000

(18) Kashiwagi, M., Ohba, M., Watanabe, H., Ishino, K., Kasahara, K., Sanai, Y., Taya, Y. and Kuroki,T.
PKCη associates with cyclin E/cdk2/p21 complex, phosphorylates p21 and inhibits cdk2 kinase in keratinocytes.
Oncogene ,19 6334-6341, 2000

(19) Yamauchi, S., Tokita, Y., Aono, S., Matsui, F., Shuo, T., Ito, H., Kato, K., Kasahara, K., Oohira, A.
Phosphorylation of neuroglycan C, a brain-specific transmembrane chondroitin sulfate proteoglycan, and its localization in the lipid rafts.
J. Biol. Chem. 277 20583-20590, 2002

(20) Kasahara, K., Watanabe, K., Kozutsumi, Y., Oohira, A., Yamamoto, T. and Sanai, Y.
Association of GPI-anchored protein TAG-1 with src-family kinase Lyn in lipid rafts of cerebellar granule cells.
Neurochemical Res. 27 823-829, 2002

(21) Hiramatsu T, Sonoda H, Takanezawa Y, Morikawa R, Ishida M, Kasahara K, Sanai Y, Taguchi R, Aoki J, Arai H.
Biochemical and molecular characterization of two phosphatidic acid-selective phospholipase A1s, mPA-PLA1 alpha and mPA-PLA1 beta.
J. Biol. Chem. 278 49438-49447, 2003

(22) Hirai M, Koizumi M, Hirai H, Hayakawa T, Yuyama K, Suzuki N, and Kasahara K
Structures and dynamics of glycosphingolipid-containing lipid mixtures as raft models of plasma membrane.
J.Phys.:Condens.Matter 17 S2965-S2977, 2005

(23) Hirai, M., Hirai, H., Koizumi, M., Kasahara, K., Yuyama, K., Suzuki, N. :
Structure of raft-model membrane by using inverse contrast variation
neutron scattering method.
Physica B: Condensed Matter, 385-386 Part2 :868-870, 2006

(24) Hirai, M., Onai, T., Koizumi, M., Hirai, H., Kasahara, K., Yuyama, K.,Suzuki, N., Inoue, K. : Permeability of water through raft model membrane clarified by time-resolved SANS and SAXS. J.Appl.Cryst. 40, s159-s164, 2007

(25) Irie, A., Takami, M., Kubo, H., Sekino-Suzuki, N., Kasahara, K., Sanai, Y. :
Heparin enhances osteoclastic bone resorption by inhibiting osteoprotegerin activity.
Bone 41, 165-174, 2007

(26) Yuyama, K., Sekino-Suzuki, N., Sanai, Y., Kasahara, K. : Translocation of activated heterotrimeric G protein Gαo to ganglioside-enriched detergent-resistant membrane rafts in developing cerebellum.
J.Biol.Chem., 282, 26392-26400, 2007

(27) Kasahara, K., Souri, M., Kaneda, M., Miki, T., Yamamoto, N., Ichinose, A. :
Impaired clot retraction in factor XIII A subunit-deficient mice.
Blood 115, 1277-1279, 2010

(28) Yuyama, K., Sekino-Suzuki, N., Yamamoto, N., Kasahara K :
Ganglioside GD3 monoclonal antibody-induced paxillin tyrosine phosphorylation and filamentous actin assembly in cerebellar growth cones
J.Neurochem. 116, 845-850, 2011

(29) Sekino-Suzuki, N., Yuyama, K., Miki, T., Kaneda, M., Suzuki, H., Yamamoto, N., Yamamoto, T., Oneyama, C., Okada,M., Kasahara, K. : Involvement of gangliosides in the process of Cbp/PAG phosphorylation by Lyn in developing cerebellar growth cones. 
J.Neurochem. 124, 514-522, 2013
(article featured as an editorial highlight J.Neurochem. 124, 432-435, 2013)

(30) Yamamoto N, Akamatsu N, Sakuraba H, Matsuno K, Hosoya R, Nogami H, Kasahara K, Mituyama S, Arai M : Novel Bernard-Soulier syndrome variants caused by compound heterozygous mutations (case I) or a cytoplasmic tail truncation (case II) of GPIbalpha.
Thromb.Res. 131, e160-e167, 2013

(31) Hirai, M., Kimura, R., Takeuchi, K., Sugiyama, M., Kasahara, K., Ohta, N., Farago, B., Stadler, A., Zaccai, G. : Change of dynamics of raft-model membrane induced by amyloid-beta protein binding.
Eur. Phys. J. E Soft Matter 36(7), 74, 2013

(32) Miki, T., Kaneda, M., Iida, K., Hasegawa, G., Murakami, M., Yamamoto, N., Asou, H., Kasahara, K. : An anti-sulfatide antibody O4 immunoprecipitates sulfatide rafts including Fyn, Lyn and the G protein alpha subunit in rat primary immature oligodendrocytes.
Glycoconj. J. 30(9) 819-823, 2013

(33) Kasahara, K., Kaneda, M., Miki, T., Iida, K., Sekino-Suzuki, N., Kawashima, I., Suzuki, H., Shimonaka, M., Arai, M., Ohni-Iwashita, Y., Kojima, S., Abe, M., Kobayashi, T., Okazaki, T., Souri, M., Ichinose, A., Yamamoto, N. : Clot retraction is mediated by factor XIII-dependent fibrin-alphaIIbbeta3-myosin axis in platelet sphingomyelin-rich membrane rafts.
Blood 122(19) 3340-3348, 2013
(article featured in INSIDE BLOOD. Blood 122, 3246-3247, 2013)

(34) Murate, M., Abe, M., Kasahara, K., Iwabuchi, K., Umeda, M., Kobayashi, T.
: Transbilayer lipid distributionin nano scale.
J. Cell Sci. 128(8) 1627-1638, 2015

(35) Kawaguchi M, Kitajima K, Kanokoda M, Suzuki H, Miyashita K, Nakajima M, Nuriya H, Kasahara K, Hara T. : Efficient production of platelets from mouse embryonic stem cells by enforced expression of Gata2 in late hemogenic endothelial cells.
Biochem Biophys Res Commun. 474(3):462-8, 2016.

(36) Ohtsuka H, Iguchi T, Hayashi M, Kaneda M, Iida K, Shimonaka M, Hara T, Arai M, Koike Y, Yamamoto N, Kasahara K. : SDF-1α/CXCR4 Signaling in Lipid Rafts Induces Platelet Aggregation via PI3 Kinase-Dependent Akt Phosphorylation.
PLoS One. 2017 Jan 10;12(1):e0169609.

Review

(1) Kuroki, T., Ikuta, T., Kasahara, K., Kohno, Y., Koizumi, H., and Chida, K.
Possible roles of protein kinase C isoforms in growth, differentiation and
carcinogenesis of keratinocytes.
In skin cancer: mechanisms and human relevance, Mukhtar, H. (ed.) CRC
Press, Inc. 121-127, 1994

(2) Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y.
Possible regulation of Lyn by glycosphingolipid in caveolae-like domains.
Kinases and phosphatases in lymphocyte and neuronal signaling
Yakura, H. (ed.) Springer-Verlag 287-288 1997

(3) Kasahara K., and Sanai Y
Possible roles of glycosphingolipids in lipid rafts.
Biophys. Chem. 82 (2/3) 121-127, 1999

(4) Kasahara K., and Sanai Y
Functional roles of glycosphingolipids in signal transduction via lipid rafts.
Glycoconjugate J. 17 152-162, 2000

(5) Kasahara K., and Sanai Y
Functional roles of glycoconjugates in signal transduction via lipid rafts.
Trend.Glycosci.Glycotech. 13(71) 251-259, 2001

(6) Kasahara K., and Sanai Y Involvement of lipid raft signaling in
ganglioside-mediated neural function.
Trend.Glycosci.Glycotech. 13(74) 587-594, 2001

(7) Yuyama K, Sekino-Suzuki N, Sanai Y and Kasahara K
Lipid rafts in cellular signaling and disease.
Trend.Glycosci.Glycotech. 15(83) 139-151, 2003

(8) Yuyama K, Sekino-Suzuki N, and Kasahara K
Signal Transduction of Heterotrimeric G Proteins in Lipid Rafts
Trend.Glycosci.Glycotech. 19(105) 19-27, 2007

(9) Kasahara K, Ui M.
G protein alpha o
UCSD-Nature Signaling Gateway Molecule Pages
Published on line: 10 Jan 2011, doi:10.1038/mp.a000976.01
http://www.signaling-gateway.org/molecule/query?afcsid=A000976

(10) Kasahara K : Lipid rafts and anti-glycolipid antibodies.
Trend Glycosci Glycotech 26 (150) 79-87, 2014

(11) Kasahara K. : Raft signaling. Glycoscience: Biology and Medicine Springer
Endo T, Seeberger PH, Hart GW, Wong CH, Taniguchi T. Eds. pp1185-1190, 2015

(12) Hayashi M, Kasahara K. : Blood Coagulation Factor XIII : A Multifunctional Transglutaminase Transglutaminases Chapter 15(Editor; Kiyotaka Hitomi, Soichi Kojima, Laszlo Fesus) Springer pp333-346 (DOI 10.1007/978-4-431-55825-5_15)

(13) Iguchi T, Kasahara K. : G alpha o Encyclopedia of Signaling Molecules, 2nd Edition Springer Sangdun Choi Eds. (DOI 10.1007/978-1-4614-6438-9_101497-1)

Link

Annual reports

1. M. Hirai, H. Hirai, M. Koizumi, N. Suzuki, K. Yuyama, and K. Kasahara.
Interaction of ganglioside with its antibody
SPring-8 User Experiment Report, 2004, 13 (2004A), 203.

2. M. Koizumi, M. Hirai, H. Hirai, K. Kasahara, N. Suzuki, and K. Yuyama.
Hierarchal map of protein unfolding observed by WAXS method
SPring-8 User Experiment Report, 2005, 14 (2004B), 189.

3. H. Hirai, M. Hirai, M. Koizumi, K. Kasahara, N. Suzuki, and K. Yuyama.
Maximum miscibility of cholesterol to ganglioside
SPring-8 User Experiment Report, 2005, 15 (2005A), 192

4. M. Hirai, K. Kasahara, K. Yuyama, S.Naoko, K. Masaharu, M. Roland,
F.Giovanna , and G. Zaccai.
Structure and dynamics of lipid raft membrane and interaction with amyloid.
Annual Report of Institut Laue-Langevin, 2005, 8-02-378.

5. M.Koizumi, H. Hirai, H. Koizumi, K. Kasahara, N. Suzuki, and M. Hirai.
Wide-angle scattering study of intramolecular structural change of
apomyoglobin and role of glycolipids in the process of amyloid formation
SPring-8 User Experiment Report, 2006, 17 (2006A), 2006A1339.

6. T. Onai, M. Hirai, M. Koizumi, K. Kasahara, N. Suzuki, and K. Yuyama.
Morphology transition of glycosphingolipid/cholesterol/phospholipid
mixtures
SPring-8 User Experiment Report, 2007, 18 (2006B), 2006B1036.

7. T. Onai, M. Hirai, M. Koizumi, H. Hirai, K. Kasahara, N. Suzuki, and K.
Yuyama.
Effect of glycosphingolipid on amyloid transition of apomyoglobin
Photon Factory Activity Report, 2007, vol. 24, 240.

8. M. Hirai, K. Kasahara, T. Onai, B. Farago, and G. Zaccai.
Effect of interaction between amyloid-protein and lipid-raft on membrane
dynamics
Annual Report of Institut Laue-Langevin, 2008, 8-02-454.

International Conferences

(1) Kasahara, K. and Sanai, Y
Association of protein tyrosine kinase with ganglioside GD3 in rat brain.
Gordon Research Conference "Structure and Biological Function of Glycolipids & Sphingolipids"
Gifu, Japan 1996, September

(2) Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y.
Association of src-family tyrosine kinase Lyn with ganglioside GD3 in rat brain.
26th Annual Meeting, Society for Neuroscience
Washington DC USA 1996 November

(3) Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y.
Association of src-family tyrosine kinase Lyn with ganglioside GD3 in rat brain.
24th Meeting of the Society for Glycobiology.
Boston USA 1996 November
Glycobiology 6(7) 752 1996

(4) Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y.
Possible regulation of src-family tyrosine kinase Lyn with ganglioside in
glycosphingolipid-microdomain on brain cell membrane.
International meeting on interactions of GPI-anchors with biological membranes
Splugen Switzerland 1997, September

(5) Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y.
Possible regulation of src-family tyrosine kinase Lyn with ganglioside
in a caveolae-like domain on brain cell membranes.
13th Tokyo Metropolitan Institute for Neuroscience International
Symposium "Kinases and phosphatases in lymphocyte and neuronal signaling"
Tokyo 1997 October

(6) Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y.
Possible regulation of src-family tyrosine kinase Lyn with ganglioside
in a caveolae-like domain on brain cell membrane.
12th Rinshoken International Conference "Cellular Signaling"
Tokyo 1997 October

(7) Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y.
Possible regulation of src-family tyrosine kinase Lyn with ganglioside
in a caveolae-like domain on brain cell membrane.
37th Annual Meeting, The American Society for Cell Biology
Washington DC USA 1997 December
Mol. Biol. Cell 8 Supplement 209a 1997

(8) Kasahara, K., Watanabe, Y., Yamamoto, T., and Sanai, Y.
Possible regulation of src-family tyrosine kinase Lyn with ganglioside
in a caveolae-like domain on brain cell membrane.
Gordon Research Conference "Glycolipid & Sphingolipid Biology"
Ventura CA USA 1998 January

(9) Kasahara, K.
Possible regulation of src-family tyrosine kinase Lyn by ganglioside
in glycosphingolipid-microdomain on brain cell membrane.
The 8th ATI International Forum
The Second Membrane Research Forum Nagoya 1998 March

(10) Kasahara, K.
Regulation of GPI-anchored neural cell adhesion molecule TAG-1
signaling by glycosphingolipid in membrane domains.
The Third Membrane Research Forum Nagoya 1999 March

(11) Kasahara, K., Watanabe, K., Yamamoto, T., and Sanai, Y.
Involvement of glycosphingolipid in GPI-anchored neural cell adhesion
molecule TAG-1 signaling at lipid rafts / caveolae membrane
XV International Symposium on Glycoconjugates (Glyco XV)Tokyo Japan 1999
Glycoconjugate Journal 16 S63 (1999) (Symposium)

(12) Kasahara, K., and Sanai, Y.
Involvement of glycosphingolipid in GPI-anchored neural cell adhesion
molecule TAG-1 signaling via src-family tyrosine kinase Lyn in lipid rafts
Tokushima Symposium "New frontier of glyco- and lipid-biology toward the
twenty-first century" Tokushima Japan 1999 August (invited)

(13) Kasahara, K., Watanabe, K., Yamamoto, T., and Sanai, Y.
Regulation of GPI-anchored neural cell adhesion molecule TAG-1 signaling
via src-family tyrosine kinase Lyn by glycosphingolipids in lipid rafts
39 th American Society for Cell Biology Annual Meeting
Washington DC USA 1999 December
Mol. Biol. Cell 10 Supplement 306a (1999)

(14) Kasahara, K.
Involvement of glycosphingolipid in GPI-anchored neural cell adhesion
molecule TAG-1 signaling via src-family kinase Lyn in lipid rafts.
Gordon Research Conferences “Glycolipid & Sphingolipid Biology”
Italy 2000 May 14-19 (invited)

(15) Kasahara, K.
Involvement of glycosphingolipids in GPI-anchored neuronal cell adhesion
molecule TAG-1 signaling via src-family kinase Lyn in lipid rafts
Joint Swiss-Japanese Scientific Seminar Synthesis and trafficking of
glycolipids and Glycolipid anchored proteins
Switzerland 2001 March 14-17 (invited)

(16) Kasahara K
Glycosphingolipid binding proteins and membrane microdomain signaling
The Fifth Membrane Research Forum, Nagoya 2001 June

(17) Kasahara, K.
Association of raft transmembrane protein Cbp with ganglioside.
Gordon Research Conferences “Glycolipid & Sphingolipid Biology”
Ventura CA USA 2002.1.27-31

(18) Kasahara, K.
Glycosphingolipid binding protein and lipid raft signaling
The Sixth Membrane Research Forum, Nagoya 2002 November

(19) Kasahara K:Association of heterotrimeric G protein Go with lipid rafts
The 7th Membrane Research Forum, 2003 August Nagoya

(20) Kohei Yuyama, Naoko Suzuki, Yutaka Sanai and Kohji Kasahara:
Association of heterotrimeric G protein Goα with lipid rafts in rat cerebellum
The 6th Conference of Asia-Pacific International Molecular Biology Network
2003 November Tokyo

(21) Kasahara K. “Signal transduction by GPI-anchored neuronal cell adhesion molecule TAG-1 in lipid rafts”
“Symposium on Glyco-Neurobiology---Glycolipids, Glycoproteins, and other Glycoforms”-A Satellite Meeting for the 2003 International Society of Neurochemistry Annual Meeting (February 8 to 11, 2004, Taipei, Taiwan) (invited)

(22) Kasahara K “Association of heterotrimeric G protein Go with lipid rafts in rat cerebellum” Sapporo Sphingolipid Symposium July 21-23 2004 Sapporo (invited)

(23) Yuyama K, Suzuki N, Sanai Y, Kasahara K: Activity-dependent association of trimeric G protein Goα with ganglioside-enriched lipid rafts in rat cerebellum
Gordon Research Conference “Glycolipid & Sphingolipid Biology” 2004.7.25-31 Hyogo

(24) Kasahara K: Ganglioside binding proteins and lipid raft signaling in neurons
Gordon Research Conference 2004.7.25-31 Hyogo

(25) Kasahara K, Suzuki N, Yuyama K, Sanai Y.:
Concentration of carbohydrates in lipid raft fraction of rat cerebellum.
US/Japan Glyco 2004 (Joint Meeting of Society for Glycobiology and Japanese Society of Carbohydrate Research) 2004.11.19 Honolulu USA

(26) Yuyama K, Suzuki N, Sanai Y, Kasahara K:
Activation-dependent recruitment of trimeric G protein Goα to lipid rafts in rat cerebellar neurons.
US/Japan Glyco 2004 (Joint Meeting of Society for Glycobiology and Japanese Society of Carbohydrate Research) 2004.11.19 Honolulu USA

(27) Suzuki N, Yuyama K, Sanai Y, Kasahara K.:
Developmental regulation of lipid raft signaling in the rat cerebellum
US/Japan Glyco 2004 (Joint Meeting of Society for Glycobiology and Japanese Society of Carbohydrate Research) 2004.11.19 Honolulu USA

(28) Kasahara K: Translocation of activated heterotrimeric G protein Goα to lipid rafts in cerebellar neurons
8th Membrane Research Forum 2004.11.24 Nagoya

(29) Kasahara K: Translocation of activated heterotrimeric G protein Goα to ganglioside-enriched detergent-resistant membrane rafts in developing cerebellum.
9th Membrane Research Forum 2006.3.16 Kyoto

(30) Yuyama,K., Sekino-Suzuki, N., Kaneda, M., Iida, K., Hoshino, M., Sanai, Y. and
Kasahara, K.: Translocation of Activated Heterotrimeric G Protein Goα to Ganglioside-Enriched Detergent-Resistant Membrane Rafts in Cerebellar Neurons
20th IUBMB International Congress of Biochemistry and Molecular Biology

(31) Kasahara K., Yuyama, K., Sekino-Suzuki, N. “Translocation of activated heterotrimeric G Protein Goα to lipid rafts in cerebellar neurons” Japan-Switzerland 2nd Joint Seminar 2007.2.1. Tsukuba

(32) Kasahara ,K., Hishino, M., Ichinose, A., Yamamoto, N., Kaneda, M. :Association of fibrin with lipid rafts of blood platelets by thrombin Glycobiology and Sphingobiology 2007 –Hakomori Commemorative Forum- 2007.2.27-3.1. Tokushima.

(33) Kasahara K : Translocation of fibrin to lipid rafts of blood platelets by thrombin 11th Membrane Research Forum 2008.2.20-22 Kyoto

(34) Ichinose A, Kasahara K, Kaetsu H, Souri M. : Moving outside: Translocation of a ‘cytosolic’ transglutaminase the A subunit of coagulation factor XIII 34th JSBBA Symposium on chemistry and biology 2008.9.27. Nagoya

(35) Kasahara K : Translocation of fibrin to lipid rafts of blood platelets and clot retraction. 59th FCCA Seminar/ Institute for Environmental and Gender-specific Medicine Workshop 2009. 2009.10.20. Tokyo

(36) Kasahara K : Factor XIII-dependent-translocation of fibrin to blood platelet rafts and clot retraction The 27th Naito Conference “Membrane Dynamics and Lipid Biology [I]” 2010.6.29-7.2 Sapporo

(37) Kasahara K : Fibrin-integrin-myosin signalingaxis in platelet membrane rafts The 30th Naito Conference “Membrane Domains, Droplets and Diseases” 2011.6.29-7.1 Sapporo

(38) Kasahara K, Kaneda M, Miki T, Iida K, Suzuki H, Hara Y, Shimonaka M, Arai M, Kobayashi T, Ichinose A, Yamamoto N : Translocation of fibrin and myosin into platelet membrane rafts is an important process for clot retraction via a functional property of GPIIb/IIIa. XXIII Congress of the International Society on Thrombosis and Haemostasis. 2011.7.24-28. Kyoto Japan

(39) Kasahara K. : Fibrin-associated platelet rafts function as platform for clot retraction. Gordon Research Conference “Glycolipid & Sphingolipid Biology” 2012.4.22-27 Italy

(40) Kasahara K. : Involvement of ganglioside GD3-raft signaling in the growth cone behavior of cerebellar granule neurons. 22nd International Symposium on Glycoconjugates. 2013.6.23-28. Dalian China (Oral presentation)

(41) Kasahara K, Ichinose A, Yamamoto N. : Clot retraction is mediated by factor XIII-dependent fibrin-alphaIIbbeta3-myosin axis in platelet sphingomyelin-rich membrane rafts. Keystone Symposia "New Frontiers in the Discovery and Treatment of Thrombosis" 2014.1.26-30. Colorado USA (Oral presentation)

(42) Kasahara K. : Clot retraction is mediated by factor XIII-dependent fibrin -alphaIIbbeta3 -myosin axis in platelet sphingomyelin-rich membrane rafts.
58th Annual Meeting Society of Thrombosis and Haemostasis Research, 2014.2.12-15 Vienna, Austria

(43) Kasahara K : Clot retraction is mediated by factor XIII-dependent fibrin -alphaIIbbeta3 -myosin axis in platelet sphingomyelin-rich membrane rafts.
BIT’s 5th World Gene Convention, 2014.11.13-16. Haikou China (invited)

(44) Kasahara K. : Fibrin Clot Retraction is Mediated by Platelet Membrane Rafts
1st Korea-Japan Bioactive Lipid Joint Symposium, 2016.5.11-13 Jeju, Korea








三量体Gタンパク質Goが活性化すると 、、、αサブユニットが脂質ラフトに移行し 、、、小脳顆粒神経細胞の成長円錐が、、、退縮する。
詳しくはこちら


ラフトモデル抜粋.jpg
脂質ラフトとは何か?
詳しくはこちら