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Neuroscience(Cooperating field)Neuroscience


Cell morphology and polarity are essential for the biological activity of the cells and for their specific roles in tissue and organs. Cells gain these morphology and polarity by intra/intercellular communications and connecting extracellular matrixes and neighboring cells. Various diseases such as the cardiovascular diseases, cancers, and nervous/psychological disorders will occur by the disfunciton of the cell morphology and polarity. To understand the regulation of cell morphology, motility, adhesion, and polarity is indispensable not only to improve molecular biology but also to establish the cause and treatment of various diseases. In our laboratory, we are trying to clarify the etiology of cardiovascular diseases and nervous/psychological disorders at cellular level by understanding the molecular mechanisms of cell morphology, motility, adhesion, and polarity.

Research Projects

Regulation of the cytoskeleton by small GTPase Rho and its effector molecules

Fig. 1

Model for regulation of MLC phosphorylation by Rho, Rho-kinase, and myosin phosphatase. MLC, myosin light chain; cat, catalytic subunit; MBS, myosin-binding subunit.

Dynamic rearrangements of the cytoskeleton and cell adhesion are required for various cellular processes such as shape changes, migration and cytokinesis. These temporal and spatial reorganizations of cell structure and cell contacts can be stimulated by extracellular signals, including growth factors, hormones, and other biologically active substances. The cytoskeleton consists mainly of three components: actin filaments, microtubules, and intermediate filaments. Cell-cell and cell-substratum contacts are mediated by adhesion molecules, such as cadherins and integrins with their associated cytoplasmic proteins. Rho is a small GTPase, and thought to be the molecular switch to mediate signals to various molecules. Rho has been implicated in the formation of stress fibers and focal adhesions, cell morphology, and smooth muscle contraction, downstream of extracellular signals, such as lysophosphatidic acid.

Rho-kinase is able to regulate the phosphorylation of MLC by the direct phosphorylation of MLC and by the inactivation of myosin phosphatase through the phosphorylation of MBS. Rho-kinase and myosin phosphatase thus coordinately regulate the phosphorylation-state of MLC, which is thought to induce smooth muscle contraction and stress fiber formation in non-muscle cells (Fig. 1).

(1)Substrates of Rho-kinase Substrates for Rho-kinase

Rho-kinase phosphorylates MBS of myosin phosphatase and MLC. ERM family proteins, adducin, intermediate filaments, CRMP-2, and calponin are also substrates of Rho-kinase, and the phosphorylation-state of these proteins appears to be associated with specific cell functions. In addition to MLC, ERM family proteins and adducin are found to be substrates of both Rho-kinase and myosin phosphatase. Thus, Rho-kinase and MBS are supposed to cooperatively control the phosphorylation level of the subset of substrates and to regulate the cytoskeletal organization in vivo (Fig. 2).

(2) Regulation of the Rho-kinase activity

Rho-kinase has a putative coiled-coil domain in its middle portion and a pleckstrin homology (PH)-like domain at its C-terminal end. The PH domain is split into two regions by the insertion of the Cys-rich region. GTP-Rho interacts with the C-terminal portion of the coiled-coil domain and activates the phosphotransferase activity of Rho-kinase. The loss of the C-terminal portion of Rho-kinase makes it constitutively active, whereas the kinase-deficient form or various C-terminal portions of Rho-kinase function as dominant negative forms in the cells. The C-terminal region is a putative negative regulatory region of Rho-kinase. It is likely that the RB and PH domains interact with the catalytic domain to inactivate the enzyme in the resting state, and that the active form of Rho interacts with the RB domain, alters the conformation of Rho-kinase and thereby cancels the inhibition by the RB and PH domains in response to extracellular signals. It has been reported that arachidonic acid cancels the inhibitory effect of RB/PH region, and activates Rho-kinase in vitro (Fig. 3).

(3) Physiological functions of Rho-kinase

Rho-kinase appears to mediate a large proportion of the signals from Rho, and regulate dynamic reorganization of cytoskeletal proteins, such as stress fiber and focal adhesion formation. Several substrates of Rho-kinase have been reported and its cellular functions unraveled. Nonetheless, roles of Rho-kinase in vivo are largely unknown (Fig. 4).

(4) K/O and TG mice of Rho-kinase

Generation of K/O and TG mice of Rho-kinase is now in progress. Analyses of these mice would reveal how Rho-kinase functions in the development, differentiation, and maintenance of organisms.

(5) Diseases and Rho/Rho-kinase

The Rho/Rho-kinase-mediated pathway plays an pivotal role in vascular smooth muscle contraction, cell adhesion and cell motility, which may be involved in the pathogenesis of arteriosclerosis/atherosclerosis. Animal experiments have demonstrated that Rho-kinase inhibitors effectively suppress coronary artery spasm and that long-term inhibition of Rho-kinase inhibits the development of coronary arteriosclerotic lesions and even causes regression of coronary vascular lesions in vivo. It is possible that Rho-kinase is also involved in the pathogenesis of other forms of cardiovascular diseases. Thus, Rho-kinase would be a novel therapeutic target in treatment of cardiovascular diseases.

Fig. 2
Substrates of Rho-kinase Substrates for Rho-kinase. cat: catalytic subunit of myosin phosphatase, Ifs: intermediate filaments, ERM: ezrin/radixin/moesin family proteins.

Fig. 3
Regulation of the Rho-kinase activity.

Fig. 4
Physiological functions of Rho-kinase

Rac/Cdc42/IQGAP & cell adhesion/cell migration

Fig. 1

1. Role of Cdc42, Rac1 and IQGAP1 in Microtubule dynamics and Cell polarity Targeting and capture of microtubule (MT) plus ends at special cortical regions are essential for polarized cellular processes such as directed cell migration and polarization of axon outgrowth. In fibroblasts, MT minus ends are anchored in the MTOC, whereas MT plus ends are directed to the cell periphery and continually alternate between two phases: elongation and shrinkage (dynamic instability). Dynamic instability is thought to enable MTs to search and capture special sites in the cortex. The CLIP-170 family, EB1 family and dynein/dynactin complex (termed +Tips) specifically accumulate at the plus ends of growing MTs and seem to play critical roles in sensing cortical capture sites (Fig.1). However, a molecular explanation for how the plus ends of MTs are captured and anchored at the cell cortex remains unclear. Cdc42 and Rac1, members of the Rho family GTPases, are implicated in cell polarization during polarization of directed cell movement of fibroblasts and astrocytes. Although much is known about the regulatory mechanism of the actin cytoskeleton by Cdc42 and Rac1, little is known about whether Cdc42 and Rac1 regulate cell polarity through the reorganization of MTs.
We found that IQGAP1, an effector of Rac1 and Cdc42 and an actin-binding protein, directly interacts with CLIP-170 and that activated Rac1 and Cdc42 form a tripartite complex with IQGAP1/CLIP-170. Activated Rac1 and Cdc42 could provide docking sites for MT plus ends at the cortex through IQGAP1 and CLIP-170 and reinforce cell polarization by establishing a polarized MT array.

Proposed model that Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170 (Fig. 2)

When the cells are stimulated with extracellular signals, Cdc42 and Rac1 are activated at special cortical region. Activated Cdc42 and Rac1 could determine the position of IQGAP1. Then, IQGAP1 together with Cdc42 and Rac1 capture the plus ends of MTs through CLIP-170. This mechanism may account for how MTs are targeted to the leading edge, where MTs play critical role in transport of specific proteins and vesicles for cell polarisation.

An IQGAP1 mutant (T1050AX2), defective in Rac1/Cdc42 binding, induces multiple leading edges (Fig. 3)
Since T1050AX2 bound to CLIP-170 with higher affinity than wild type IQGAP1 in a Rac1 and Cdc42-independent manner, it is expected that T1050AX2 functions as a constitutively active mutant of IQGAP1. About 10% of the cells expressing T1050AX2 induced multiple leading edges and displayed multipolarized morphology. Judging from the fact that T1050AX2 localized at cortical region in a Rac1/Cdc42-independent manner and induced multiple leading edges, it is possible that T1050AX2 creates multiple target sites for CLIP-170-associated MT plus ends.

Cell scattering (Fig. 4) provides an example of dynamic rearrangement of cell-cell adhesion. TPA (12-O-tetradecanoylphorbol-13-acetate) or HGF (hepatocyte growth factor) induces membrane ruffling (after 5-15 min treatment), centrifugal spreading of Mardin-Dargy canine kidney II (MDCKII) cells in colonies, cell-cell dissociation, and ultimately cell scattering (after 2-6 hr treatment). This dynamic process is determined by a change in the balance between the cell-cell adhesive activity and cell motility; loss of cell-cell adhesion and increased cell motility promote cell scattering. During scattering, Rac1/Cdc42/IQGAP1 system might be involved in loss of cell-cell adhesion (Inside-Out signaling). The other hand, Is the Rac1/Cdc42/IQGAP1 system involved in the establishment of cadherin-mediated cell-cell adhesion? Does cadherin work as a signaling receptor? We studied about these question and hypothesized the signal transduction from cadherin (Outside-In signaling).

Model: signal transduction during establishment of cadherin-mediated cell-cell adhesion

Dynamics of Rac1 localization during reorganization of cadherin-mediated cell-cell adhesion. Dynamics of EGFP-Rac1 localization was analyzed by time-lapse imaging. MDCKII cells were transfected with pEGFP-Rac1. The cells were treated with 4 mM EGTA for 30 min (destruction of cadherin-mediated cell-cell adhesion). Subsequently, the cells were treated with calcium-containing medium for the indicated time (establishment of cadherin-mediated cell-cell adhesion).

Fig. 2: Proposed model that Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170

Fig. 3 An IQGAP1 mutant (T1050AX2), defective in Rac1/Cdc42 binding, induces multiple leading edges

Fig. 4 Cell scatering

Polarity and circuit formation of neuronal cell

Fig. 1: Neuronal polarity
(How does neuron form funtionally and morphologically distinct types of processes, axons and dendrites?)

Analysis of formation of neural network and polarity in neuron

During embryonic development, neurons derived from neuroepithelial cells migrate toward the pia of neuroepithelium. Neuron, which arrives at a certain place, typically generates a single axon and multiple dendrites, and results in acquiring neuronal polarity. Axons elongate to appropriate target neurons (axon guidance), and subsequently form the synapses, thereby establishing neuronal network. Our research interest is to understand the molecular mechanisms of 1) determination of axon and dendrite fate, 2) axon guidance, and 3) synaptogenesis during neuronal development.

Determination of axon and dendrite fate

Neurons contain two distinct types of processes, axons and dendrites. These processes provide the basis for the formation of complicated neuronal network in brain (Figure 1). We previously identified Collapsin response mediator protein-2 (CRMP-2) as a good substrate of Rho-kinase in brain (Arimura et al., 2000). Recent investigation in hippocampal neurons has implicated CRMP-2 in the regulation of axon formation during neuronal polarization (Inagaki et al., Nat. Neurosci., 2001, Figure 2). We are investigating how CRMP-2 determines axon and dendrite fate of neurites. We recently searched for the CRMP-2-binding proteins, and found that CRMP-2 regulates microtubule dynamics through the binding to tubulin heterodimers (Fukata et al., Nat. Cell Biol., In press). CRMP-2 regulates axonal growth and branching as a partner of tubulin heterodimer, in a fashion different from traditional MAPs. In addition to tubulin, several proteins were found to be CRMP-2-interacting molecules. We expect to clarify not only the mechanism of determination of axon and dendrite fate, but also the accumulation of CRMP-2 in the distal part of axon and the regulation of CRMP-2 activity through the analysis of CRMP-2-interacting molecules. We are also trying to evaluate physiological as well as pathological roles of CRMP-2 by using transgenic mouse of CRMP-2 and hypoglossal neurons after axotomy, which is the model system of axon injury and neuronal regeneration. We hope that these studies contribute toward therapeutics of Alzheimer and axon injury diseases.

Mechanism of axon guidance

The change of shape and motility of growth cone in response to guidance cues plays central role for axon guidance. Our and other laboratories found that the Rho/Rho-kinase pathway promotes neurite retraction via the phosphorylation of myosin light chain of myosin II downstream of lysophosphatidic acid (LPA) and Ephrin. Furthermore, we found that CRMP-2 is a good substrate of Rho-kinase in brain (Arimura et al., 2000). Rho-kinase phosphorylates CRMP-2 at the specific residue in response to LPA but not to semaphorin 3A in DRG neurons. CRMP-2 phosphorylation by Rho-kinase participates in growth cone collapse by LPA (Figure 3). We are analyzing how the phosphorylation of CRMP-2 by Rho-kinase is involved in growth cone collapse and axon guidance.

Mechanism of synaptogenesis

Axon and dendrite extension, and synaptogenesis are essential for the maturation of neuron and the development of the nervous system. It is believed that Rho family GTPases (Rho, Rac, Cdc42) in neurons are implicated in the growth and retraction of axon and dendrite and synaptogenesis during the formation of neuronal network. However, how Rho family GTPases regulate axonal and dendritic elongation, and synaptogenesis is largely unknown. We focus on the effector of Rho family GTPases and attempt to solve this issue.

Fig. 2: CRMP-2 regulates axon formation

CRMP-2 overexpressing neurons bear more than 1 axon in cultured hippocampal neurons.
Myc-CRMP-2 (anti-myc Ab.): Green
Axonal marker (Tau-1 Ab.): Red

Fig. 3: Rho-kinase plays an essential role in LPA-induced growth cone collapse.

A growth cone of chick DRG neurons collapse by LPA stimulation.
Dominant negative form of Rho-kinase prevents the LPA-inudced growth cone collapse.
A CRMP-2 mutant, in which Rho-kinase phosphorylation site, also inhibits growth cone collapse (data not shown).

Psychiatric disorders

Fig.: Role of DISC1 in Nudel & Grb2 transport for axon growth

DISC1 connects NUDEL/LIS1/14-3-3e complex to kinsein-1 and positively regulates their transport into the distal part of axon.
Analogously, DISC1 also links Grb2 to kinesin-1 and regulates the axonal transport of Grb2.
Thus, DISC1 functions as cargo adapter by linking its binding partners to kinesin-1.
The proper transport of these molecules into axon is required for axon elongation.

Elucidation of molecular pathogenesis of schizophrenia by analyzing susceptibility genes such as DISC1

The etiological mechanisms of psychiatric disorders such as schizophrenia remain largely esoteric, although multiple hypotheses (e.g., dysfunction of dopamine; glutamate or serotonin; neurodevelopmental disorders; stress during pregnancy; viral infection) have been proposed (Harrison and Weinberger, 2005; Lewis and Gonzalez-Burgos, 2006).

Dissection of the pathways centered on promising risk factors such as DISC1 will help us to better understand the pathogenesis of these disorders. The DISC1 gene locus was originally identified at the breakpoint of a balanced (1;11) (q42; q14) chromosome translocation that co-segregates with schizophrenia, bipolar disorder, and recurrent major depression in a large Scottish family (Blackwood et al., 2001; Millar et al., 2000). Further analysis indicated that inheritance of the translocation is causal and increases the risk of these psychiatric disorders 50-fold (Blackwood et al., 2001).

Genetic association studies in several ethnic groups have since revealed that DISC1 is a major risk factor for psychiatric disorders, including schizophrenia and mood disorders (Hodgkinson et al., 2004). Studies of clinical subjects have shown that genetic variations in DISC1 influence brain function and anatomy (Callicott et al., 2005).

Both anatomical and behavioral analyses of mice with DISC1 dysfunction, including animals with missense mutations (Clapcote et al., 2007), overexpression of truncated forms of DISC1 (Hikida et al., 2007; Li et al., 2007b; Pletnikov et al., 2008; Shen et al., 2008), and deletion of certain isoforms (Ishizuka et al., 2007; Koike et al., 2006; Kvajo et al., 2008), reveal phenotypes such as schizophrenia and/or depression-related phenotypes.

To understand the molecular function of DISC1, several groups have isolated DISC1-interacting proteins including nuclear distribution gene E homolog-like 1 (NDEL1), growth factor receptor-bound protein 2 (GRB2), glycogen synthase kinase 3b (GSK3b) , lissencephaly-1 (LIS1), kinesin family member 5B (KIF5B), fasciculation and elongation protein zeta 1 (FEZ1), girdin, huntingtin-associated protein interacting protein, and Phosphodiesterase 4B (Camargo et al., 2007; Enomoto et al., 2009; Hayashi-Takagi et al.; Mao et al., 2009; Millar et al., 2005; Miyoshi et al., 2003; Ozeki et al., 2003; Shinoda et al., 2007; Taya et al., 2007).

These efforts have given us a platform on which to interrogate the processes and pathways affected by DISC1. In vitro studies, studies in intact cells, and analysis of mutant animals have all shown that DISC1 is involved in neurogenesis, neuronal migration, axon/dendrite formation, and synapse formation through interactions with various partners (Brandon et al., 2009). DISC1 is thus considered to be a scaffold protein that regulates certain pathways (Chubb et al., 2008), but it is still unclear how DISC1 acts at the molecular level in its various functions including synaptic plasticity.

To understand the molecular functions of DISC1, we are currently obtaining a comprehensive set of proteins interacting with DISC1 by proteomic approach, and analyzing their patho-physiological functions. Moreover, we are generating knockout and transgenic mice of the DISC1 genes.

Faculty Members

Kozo Kaibuchi Professor Neuroscience/Molecular Pharmacology
Mutsuki Amano Associate Professor Neuroscience/Molecular Pharmacology
Tomoki Nishioka Assistant professor Neuroscience/Molecular Pharmacology
Daisuke Tsuboi Assistant professor Neuroscience/Molecular Pharmacology
Keisuke Kuroda Assistant professor Neuroscience/Molecular Pharmacology
Keita Tsujimura Assistant professor Neuroscience/Molecular Pharmacology
Yasuhiro Funahashi Assistant professor Neuroscience/Molecular Pharmacology


  • 2016
    1. Nagai T, Yoshimoto J, Kannon T, Kuroda K, Kaibuchi K. Phosphorylation Signals in Striatal Medium Spiny Neurons. Trends Pharmacol Sci, 2016; 37: 858-871.
    2. Nagai T, Nakamuta S, Kuroda K, Nakauchi S, Nishioka T, Takano T, Zhang X, Tsuboi D, Funahashi Y, Nakano T, Yoshimoto J, Kobayashi K, Uchigashima M, Watanabe M, Miura M, Nishi A, Kobayashi K, Yamada K, Amano M, Kaibuchi K. Phosphoproteomics of the Dopamine Pathway Enables Discovery of Rap1 Activation as a Reward Signal In Vivo. Neuron, 2016; 89: 550-565.
    3. Yura Y, Amano M, Takefuji M, Bando T, Suzuki K, Kato K, Hamaguchi T, Hasanuzzaman Shohag M, Takano T, Funahashi Y, Nakamuta S, Kuroda K, Nishioka T, Murohara T, Kaibuchi K. Focused Proteomics Revealed a Novel Rho-kinase Signaling Pathway in the Heart. Cell Struct Funct, 2016; 41: 105-120.
    4. Matsuzawa K, Akita H, Watanabe T, Kakeno M, Matsui T, Wang S, Kaibuchi K. PAR3-aPKC regulates Tiam1 by modulating suppressive internal interactions. Mol Biol Cell, 2016; 27: 1511-1523.
    5. Amano M, Nishioka T, Yura Y, Kaibuchi K. Identification of Protein Kinase Substrates by the Kinase-Interacting Substrate Screening (KISS) Approach. Curr Protoc Cell Biol, 2016; 72: 14 16 11-14 16 12.
  • 2015
    1. Xu C, Funahashi Y, Watanabe T, Takano T, Nakamuta S, Namba T, Kaibuchi K. Radial Glial Cell-Neuron Interaction Directs Axon Formation at the Opposite Side of the Neuron from the Contact Site. J Neurosci, 2015; 35: 14517-14532.
    2. Watanabe T, Kakeno M, Matsui T, Sugiyama I, Arimura N, Matsuzawa K, Shirahige A, Ishidate F, Nishioka T, Taya S, Hoshino M, Kaibuchi K. TTBK2 with EB1/3 regulates microtubule dynamics in migrating cells through KIF2A phosphorylation. J Cell Biol, 2015; 210: 737-751.
    3. Tsuboi D, Kuroda K, Tanaka M, Namba T, Iizuka Y, Taya S, Shinoda T, Hikita T, Muraoka S, Iizuka M, Nimura A, Mizoguchi A, Shiina N, Sokabe M, Okano H, Mikoshiba K, Kaibuchi K. Disrupted-in-schizophrenia 1 regulates transport of ITPR1 mRNA for synaptic plasticity. Nat Neurosci, 2015; 18: 698-707.
    4. Takano T, Xu C, Funahashi Y, Namba T, Kaibuchi K. Neuronal polarization. Development, 2015; 142: 2088-2093.
    5. Shohag MH, Nishioka T, Ahammad RU, Nakamuta S, Yura Y, Hamaguchi T, Kaibuchi K, Amano M. Phosphoproteomic Analysis Using the WW and FHA Domains as Biological Filters. Cell Struct Funct, 2015; 40: 95-104.
    6. Nishioka T, Shohag MH, Amano M, Kaibuchi K. Developing novel methods to search for substrates of protein kinases such as Rho-kinase. Biochim Biophys Acta, 2015; 1854: 1663-1666.
    7. Namba T, Funahashi Y, Nakamuta S, Xu C, Takano T, Kaibuchi K. Extracellular and Intracellular Signaling for Neuronal Polarity. Physiol Rev, 2015; 95: 995-1024.
    8. Matsui T, Watanabe T, Matsuzawa K, Kakeno M, Okumura N, Sugiyama I, Itoh N, Kaibuchi K. PAR3 and aPKC regulate Golgi organization through CLASP2 phosphorylation to generate cell polarity. Mol Biol Cell, 2015; 26: 751-761.
    9. Hamaguchi T, Nakamuta S, Funahashi Y, Takano T, Nishioka T, Shohag MH, Yura Y, Kaibuchi K, Amano M. In vivo screening for substrates of protein kinase A using a combination of proteomic approaches and pharmacological modulation of kinase activity. Cell Struct Funct, 2015; 40: 1-12.
    10. Amano M, Hamaguchi T, Shohag MH, Kozawa K, Kato K, Zhang X, Yura Y, Matsuura Y, Kataoka C, Nishioka T, Kaibuchi K. Kinase-interacting substrate screening is a novel method to identify kinase substrates. J Cell Biol, 2015; 209: 895-912.
  • 2014
    1. Namba T, Kibe Y, Funahashi Y, Nakamuta S, Takano T, Ueno T, Shimada A, Kozawa S, Okamoto M, Shimoda Y, Oda K, Wada Y, Masuda T, Sakakibara A, Igarashi M, Miyata T, Faivre-Sarrailh C, Takeuchi K, Kaibuchi K. Pioneering axons regulate neuronal polarization in the developing cerebral cortex. Neuron, 2014; 81: 814-829.
    2. Kakeno M, Matsuzawa K, Matsui T, Akita H, Sugiyama I, Ishidate F, Nakano A, Takashima S, Goto H, Inagaki M, Kaibuchi K, Watanabe T. Plk1 phosphorylates CLIP-170 and regulates its binding to microtubules for chromosome alignment. Cell Struct Funct, 2014; 39: 45-59.
  • 2013
    1. Funahashi Y, Namba T, Nakamuta S, Kaibuchi K. Neuronal polarization in vivo: Growing in a complex environment. Curr Opin Neurobiol, 2014; 27: 215-223.
    2. Funahashi Y, Namba T, Fujisue S, Itoh N, Nakamuta S, Kato K, Shimada A, Xu C, Shan W, Nishioka T, Kaibuchi K. ERK2-mediated phosphorylation of Par3 regulates neuronal polarization. J Neurosci, 2013; 33: 13270-13285.
  • 2012
    1. Wang S, Watanabe T, Matsuzawa K, Katsumi A, Kakeno M, Matsui T, Ye F, Sato K, Murase K, Sugiyama I, Kimura K, Mizoguchi A, Ginsberg MH, Collard JG, Kaibuchi K. Tiam1 interaction with the PAR complex promotes talin-mediated Rac1 activation during polarized cell migration. J Cell Biol, 2012; 199: 331-345.
    2. Kato K, Yazawa T, Taki K, Mori K, Wang S, Nishioka T, Hamaguchi T, Itoh T, Takenawa T, Kataoka C, Matsuura Y, Amano M, Murohara T, Kaibuchi K. The inositol 5-phosphatase SHIP2 is an effector of RhoA and is involved in cell polarity and migration. Mol Biol Cell, 2012; 23: 2593-2604.
  • 2011
    1. Sato K, Watanabe T, Wang S, Kakeno M, Matsuzawa K, Matsui T, Yokoi K, Murase K, Sugiyama I, Ozawa M, Kaibuchi K. Numb controls E-cadherin endocytosis through p120 catenin with aPKC. Mol Biol Cell, 2011; 22: 3103-3119.
    2. Namba T, Nakamuta S, Funahashi Y, Kaibuchi K. The role of selective transport in neuronal polarization. Dev Neurobiol, 2011; 71: 445-457.
    3. Nakamuta S, Funahashi Y, Namba T, Arimura N, Picciotto MR, Tokumitsu H, Soderling TR, Sakakibara A, Miyata T, Kamiguchi H, Kaibuchi K. Local application of neurotrophins specifies axons through inositol 1,4,5-trisphosphate, calcium, and Ca2+/calmodulin-dependent protein kinases. Sci Signal, 2011; 4: ra76.
    4. Kuroda K, Yamada S, Tanaka M, Iizuka M, Yano H, Mori D, Tsuboi D, Nishioka T, Namba T, Iizuka Y, Kubota S, Nagai T, Ibi D, Wang R, Enomoto A, Isotani-Sakakibara M, Asai N, Kimura K, Kiyonari H, Abe T, Mizoguchi A, Sokabe M, Takahashi M, Yamada K, Kaibuchi K. Behavioral alterations associated with targeted disruption of exons 2 and 3 of the Disc1 gene in the mouse. Hum Mol Genet, 2011; 20: 4666-4683.
  • 2010
    1. Itoh N, Nakayama M, Nishimura T, Fujisue S, Nishioka T, Watanabe T, Kaibuchi K. Identification of focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3-kinase) as Par3 partners by proteomic analysis. Cytoskeleton (Hoboken), 2010; 67: 297-308.
    2. Amano M, Tsumura Y, Taki K, Harada H, Mori K, Nishioka T, Kato K, Suzuki T, Nishioka Y, Iwamatsu A, Kaibuchi K. A proteomic approach for comprehensively screening substrates of protein kinases such as Rho-kinase. PLoS One, 2010; 5: e8704.
  • 2009
    1. Watanabe T, Sato K, Kaibuchi K. Cadherin-mediated intercellular adhesion and signaling cascades involving small GTPases. Cold Spring Harb Perspect Biol, 2009; 1: a003020.
    2. Watanabe T, Noritake J, Kakeno M, Matsui T, Harada T, Wang S, Itoh N, Sato K, Matsuzawa K, Iwamatsu A, Galjart N, Kaibuchi K. Phosphorylation of CLASP2 by GSK-3beta regulates its interaction with IQGAP1, EB1 and microtubules. J Cell Sci, 2009; 122: 2969-2979.
    3. Mori K, Amano M, Takefuji M, Kato K, Morita Y, Nishioka T, Matsuura Y, Murohara T, Kaibuchi K. Rho-kinase contributes to sustained RhoA activation through phosphorylation of p190A RhoGAP. J Biol Chem, 2009; 284: 5067-5076.
    4. Hikita T, Taya S, Fujino Y, Taneichi-Kuroda S, Ohta K, Tsuboi D, Shinoda T, Kuroda K, Funahashi Y, Uraguchi-Asaki J, Hashimoto R, Kaibuchi K. Proteomic analysis reveals novel binding partners of dysbindin, a schizophrenia-related protein. J Neurochem, 2009; 110: 1567-1574.
    5. Arimura N, Kimura T, Nakamuta S, Taya S, Funahashi Y, Hattori A, Shimada A, Menager C, Kawabata S, Fujii K, Iwamatsu A, Segal RA, Fukuda M, Kaibuchi K. Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev Cell, 2009; 16: 675-686.
    6. Arimura N, Hattori A, Kimura T, Nakamuta S, Funahashi Y, Hirotsune S, Furuta K, Urano T, Toyoshima YY, Kaibuchi K. CRMP-2 directly binds to cytoplasmic dynein and interferes with its activity. J Neurochem, 2009; 111: 380-390.
  • 2008
    1. Nakayama M, Goto TM, Sugimoto M, Nishimura T, Shinagawa T, Ohno S, Amano M, Kaibuchi K. Rho-kinase phosphorylates PAR-3 and disrupts PAR complex formation. Dev Cell, 2008; 14: 205-215.
  • 2007
    1. Wang S, Watanabe T, Noritake J, Fukata M, Yoshimura T, Itoh N, Harada T, Nakagawa M, Matsuura Y, Arimura N, Kaibuchi K. IQGAP3, a novel effector of Rac1 and Cdc42, regulates neurite outgrowth. J Cell Sci, 2007; 120: 567-577.
    2. Taya S, Shinoda T, Tsuboi D, Asaki J, Nagai K, Hikita T, Kuroda S, Kuroda K, Shimizu M, Hirotsune S, Iwamatsu A, Kaibuchi K. DISC1 regulates the transport of the NUDEL/LIS1/14-3-3epsilon complex through kinesin-1. J Neurosci, 2007; 27: 15-26.
    3. Shinoda T, Taya S, Tsuboi D, Hikita T, Matsuzawa R, Kuroda S, Iwamatsu A, Kaibuchi K. DISC1 regulates neurotrophin-induced axon elongation via interaction with Grb2. J Neurosci, 2007; 27: 4-14.
    4. Nishimura T, Kaibuchi K. Numb controls integrin endocytosis for directional cell migration with aPKC and PAR-3. Dev Cell, 2007; 13: 15-28.
    5. Arimura N, Kaibuchi K. Neuronal polarity: from extracellular signals to intracellular mechanisms. Nat Rev Neurosci, 2007; 8: 194-205.
  • 2006
    1. Yoshimura T, Arimura N, Kawano Y, Kawabata S, Wang S, Kaibuchi K. Ras regulates neuronal polarity via the PI3-kinase/Akt/GSK-3beta/CRMP-2 pathway. Biochem Biophys Res Commun, 2006; 340: 62-68.
    2. Yoshimura T, Arimura N, Kaibuchi K. Molecular mechanisms of axon specification and neuronal disorders. Ann N Y Acad Sci, 2006; 1086: 116-125.
    3. Yoshimura T, Arimura N, Kaibuchi K. Signaling networks in neuronal polarization. J Neurosci, 2006; 26: 10626-10630.
    4. Nishimura T, Yamaguchi T, Tokunaga A, Hara A, Hamaguchi T, Kato K, Iwamatsu A, Okano H, Kaibuchi K. Role of numb in dendritic spine development with a Cdc42 GEF intersectin and EphB2. Mol Biol Cell, 2006; 17: 1273-1285.
  • 2005
    1. Yoshimura T, Kawano Y, Arimura N, Kawabata S, Kikuchi A, Kaibuchi K. GSK-3beta regulates phosphorylation of CRMP-2 and neuronal polarity. Cell, 2005; 120: 137-149.
    2. Nishimura T, Yamaguchi T, Kato K, Yoshizawa M, Nabeshima Y, Ohno S, Hoshino M, Kaibuchi K. PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol, 2005; 7: 270-277.
    3. Kawano Y, Yoshimura T, Tsuboi D, Kawabata S, Kaneko-Kawano T, Shirataki H, Takenawa T, Kaibuchi K. CRMP-2 is involved in kinesin-1-dependent transport of the Sra-1/WAVE1 complex and axon formation. Mol Cell Biol, 2005; 25: 9920-9935.
    4. Arimura N, Menager C, Kawano Y, Yoshimura T, Kawabata S, Hattori A, Fukata Y, Amano M, Goshima Y, Inagaki M, Morone N, Usukura J, Kaibuchi K. Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol Cell Biol, 2005; 25: 9973-9984.
    5. Arimura N, Kaibuchi K. Key regulators in neuronal polarity. Neuron, 2005; 48: 881-884.
  • 2004
    1. Watanabe T, Wang S, Noritake J, Sato K, Fukata M, Takefuji M, Nakagawa M, Izumi N, Akiyama T, Kaibuchi K. Interaction with IQGAP1 links APC to Rac1, Cdc42, and actin filaments during cell polarization and migration. Dev Cell, 2004; 7: 871-883.
    2. Noritake J, Fukata M, Sato K, Nakagawa M, Watanabe T, Izumi N, Wang S, Fukata Y, Kaibuchi K. Positive role of IQGAP1, an effector of Rac1, in actin-meshwork formation at sites of cell-cell contact. Mol Biol Cell, 2004; 15: 1065-1076.
    3. Nishimura T, Kato K, Yamaguchi T, Fukata Y, Ohno S, Kaibuchi K. Role of the PAR-3-KIF3 complex in the establishment of neuronal polarity. Nat Cell Biol, 2004; 6: 328-334.
    4. Menager C, Arimura N, Fukata Y, Kaibuchi K. PIP3 is involved in neuronal polarization and axon formation. J Neurochem, 2004; 89: 109-118.
    5. Arimura N, Menager C, Fukata Y, Kaibuchi K. Role of CRMP-2 in neuronal polarity. J Neurobiol, 2004; 58: 34-47.
  • 2003
    1. Nishimura T, Fukata Y, Kato K, Yamaguchi T, Matsuura Y, Kamiguchi H, Kaibuchi K. CRMP-2 regulates polarized Numb-mediated endocytosis for axon growth. Nat Cell Biol, 2003; 5: 819-826.
    2. Fukata M, Nakagawa M, Kaibuchi K. Roles of Rho-family GTPases in cell polarisation and directional migration. Curr Opin Cell Biol, 2003; 15: 590-597.
  • 2002
    1. Fukata Y, Itoh TJ, Kimura T, Menager C, Nishimura T, Shiromizu T, Watanabe H, Inagaki N, Iwamatsu A, Hotani H, Kaibuchi K. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nat Cell Biol, 2002; 4: 583-591.
    2. Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, Kuroda S, Matsuura Y, Iwamatsu A, Perez F, Kaibuchi K. Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170. Cell, 2002; 109: 873-885.
  • 2001
    1. Taya S, Inagaki N, Sengiku H, Makino H, Iwamatsu A, Urakawa I, Nagao K, Kataoka S, Kaibuchi K. Direct interaction of insulin-like growth factor-1 receptor with leukemia-associated RhoGEF. J Cell Biol, 2001; 155: 809-820.
    2. Inagaki N, Chihara K, Arimura N, Menager C, Kawano Y, Matsuo N, Nishimura T, Amano M, Kaibuchi K. CRMP-2 induces axons in cultured hippocampal neurons. Nat Neurosci, 2001; 4: 781-782.
    3. Fukata M, Kaibuchi K. Rho-family GTPases in cadherin-mediated cell-cell adhesion. Nat Rev Mol Cell Biol, 2001; 2: 887-897.
  • 2000
    1. Arimura N, Inagaki N, Chihara K, Menager C, Nakamura N, Amano M, Iwamatsu A, Goshima Y, Kaibuchi K. Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse. J Biol Chem, 2000; 275: 23973-23980.
  • 1999
    1. Kaibuchi K, Kuroda S, Amano M. Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annu Rev Biochem, 1999; 68: 459-486.
  • 1997
    1. Amano M, Chihara K, Kimura K, Fukata Y, Nakamura N, Matsuura Y, Kaibuchi K. Formation of actin stress fibers and focal adhesions enhanced by Rho-kinase. Science, 1997; 275: 1308-1311.
  • 1996
    1. Kimura K, Ito M, Amano M, Chihara K, Fukata Y, Nakafuku M, Yamamori B, Feng J, Nakano T, Okawa K, Iwamatsu A, Kaibuchi K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science, 1996; 273: 245-248.
    2. Amano M, Mukai H, Ono Y, Chihara K, Matsui T, Hamajima Y, Okawa K, Iwamatsu A, Kaibuchi K. Identification of a putative target for Rho as the serine-threonine kinase protein kinase N. Science, 1996; 271: 648-650.

Research Keywords

Cell polarity、 Cell migration、 Cell adhesion、 Arteriosclerosis/Atherosclerosis、 Schizophrenia、 Signal transduction、 Small G protein、

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Department of Cell Pharmacology

Nagoya University, Graduate School of Medicine

65 Tsurumai, Showa, Nagoya, AICHI 466-8550, Japan

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