Faculty Profiles - Nakayama Masanori

Papers - Nakayama Masanori

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Examining the association between vaccine reactogenicity and antibody titer dynamics after the third dose of BNT162b2 vaccine using a mixed-effects model. International journal

Naomi Matsumoto, Hideharu Hagiya, Masanori Nakayama, Masanori Furukawa, Toshiharu Mitsuhashi, Soshi Takao, Fumio Otsuka, Takashi Yorifuji

Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy 29 ( 1 ) 39 - 42 2023.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: To mitigate the COVID-19 pandemic, many countries have recommended the use of booster vaccinations. The relationship between the degree of adverse vaccine reactions and elevated antibody titers is of interest; however, no studies have investigated the temporal changes in antibody titers based on repeated measurements after a third dose of the BNT162b2 vaccine. METHODS: This prospective longitudinal cohort study was conducted with 62 healthcare workers who received a third dose of the BNT162b2 at Okayama University Hospital, Japan. Venous blood draw and fingertip whole blood test sample collection were conducted at the early (3-13 days) and 1-month time points; only FWT sample collection was conducted at the 2-month time point. Information on adverse reactions within 1 week after vaccination was also obtained. The association between fever of 37.5 °C or higher and antibody titers after the third dose of BNT162b2 was examined using a mixed-effects model and Poisson regression with robust variance. RESULTS: A trend toward higher antibody titers in the early period after vaccination was observed in the febrile individuals, but the differences were not significant at 1 and 2 months post-vaccination (the partial regression coefficient for fever was 8094.3 [-1910.2, 18,098.8] at 1 month after vaccination, and 1764.1 [-4133.9, 7662.1] at 2 months after vaccination in the adjusted models). CONCLUSION: The findings suggest that the presence of fever after the third vaccine does not predict a sustained elevation in serum antibody titers.

DOI： 10.1016/j.jiac.2022.09.012

Association Between Fever and Antibody Titer Trends After a Third Dose of the mRNA-1273 Vaccine.

Naomi Matsumoto, Tomoka Kadowaki, Rumi Matsuo, Ayako Sasaki, Chikara Miyaji, Chigusa Higuchi, Masanori Nakayama, Yasue Sakurada, Hideharu Hagiya, Soshi Takao, Fumio Otsuka, Takashi Yorifuji

Journal of epidemiology 32 ( 12 ) 567 - 569 2022.12

Early-stage antibody kinetics after the third dose of BNT162b2 mRNA COVID-19 vaccination measured by a point-of-care fingertip whole blood testing. International journal

Hideharu Hagiya, Yasuhiro Nakano, Masanori Furukawa, Naruhiko Sunada, Toru Hasegawa, Yasue Sakurada, Kou Hasegawa, Koichiro Yamamoto, Hiroko Ogawa, Takafumi Obara, Kouhei Ageta, Naomi Matsumoto, Rumi Matsuo, Tomoka Kadowaki, Akihito Higashikage, Takao Hikita, Takashi Yorifuji, Shinichi Toyooka, Yoshinobu Maeda, Yoshinori Yokokura, Fumio Otsuka, Masanori Nakayama

Scientific reports 12 ( 1 ) 20628 - 20628 2022.11

Language：English Publishing type：Research paper (scientific journal)

Amid the Coronavirus Disease 2019 pandemic, we aimed to demonstrate the accuracy of the fingertip whole blood sampling test (FWT) in measuring the antibody titer and uncovering its dynamics shortly after booster vaccination. Mokobio SARS-CoV-2 IgM & IgG Quantum Dot immunoassay (Mokobio Biotechnology R&D Center Inc., MD, USA) was used as a point-of-care FWT in 226 health care workers (HCWs) who had received two doses of the BNT162b2 mRNA vaccine (Pfizer-BioNTech) at least 8 months prior. Each participant tested their antibody titers before and after the third-dose booster up to 14-days. The effect of the booster was observed as early as the fourth day after vaccination, which exceeded the detection limit (> 30,000 U/mL) by 2.3% on the fifth day, 12.2% on the sixth day, and 22.5% after the seventh day. Significant positive correlations were observed between the pre- and post-vaccination (the seventh and eighth days) antibody titers (correlation coefficient, 0.405; p < 0.001). FWT is useful for examining antibody titers as a point-of-care test. Rapid response of antibody titer started as early as the fourth day post-vaccination, while the presence of weak responders to BNT162b2 vaccine was indicated.

DOI： 10.1038/s41598-022-24464-3

Poor vaccine responsiveness towards third-dose mRNA vaccine of COVID-19 in Japanese older people. International journal

Hideharu Hagiya, Takao Hikita, Tomohiro Habu, Masaki Asada, Takashi Yorifuji, Shinichi Toyooka, Fumio Otsuka, Masanori Nakayama

The Journal of infection 85 ( 4 ) 436 - 480 2022.10

Vasohibin-1が誘導する微小管の翻訳後修飾を介した受容体エンドサイトーシス阻害と新規脈管新生抑制機構

小林美穂, 若林育海, 藤原花汐, 鈴木康弘, 中山雅敬, 佐藤靖史, 渡部徹郎

リンパ学 44 ( 2 ) 65 - 69 2021.12

Numerical evaluation reveals the effect of branching morphology on vessel transport properties during angiogenesis. International journal

Fatemeh Mirzapour-Shafiyi, Yukinori Kametani, Takao Hikita, Yosuke Hasegawa, Masanori Nakayama

PLoS computational biology 17 ( 6 ) e1008398 2021.6

Language：English Publishing type：Research paper (scientific journal)

Blood flow governs transport of oxygen and nutrients into tissues. Hypoxic tissues secrete VEGFs to promote angiogenesis during development and in tissue homeostasis. In contrast, tumors enhance pathologic angiogenesis during growth and metastasis, suggesting suppression of tumor angiogenesis could limit tumor growth. In line with these observations, various factors have been identified to control vessel formation in the last decades. However, their impacts on the vascular transport properties of oxygen remain elusive. Here, we take a computational approach to examine the effects of vascular branching on blood flow in the growing vasculature. First of all, we reconstruct a 3D vascular model from the 2D confocal images of the growing vasculature at postnatal day 5 (P5) mouse retina, then simulate blood flow in the vasculatures, which are obtained from the gene targeting mouse models causing hypo- or hyper-branching vascular formation. Interestingly, hyper-branching morphology attenuates effective blood flow at the angiogenic front, likely promoting tissue hypoxia. In contrast, vascular hypo-branching enhances blood supply at the angiogenic front of the growing vasculature. Oxygen supply by newly formed blood vessels improves local hypoxia and decreases VEGF expression at the angiogenic front during angiogenesis. Consistent with the simulation results indicating improved blood flow in the hypo-branching vasculature, VEGF expression around the angiogenic front is reduced in those mouse retinas. Conversely, VEGF expression is enhanced in the angiogenic front of hyper-branching vasculature. Our results indicate the importance of detailed flow analysis in evaluating the vascular transport properties of branching morphology of the blood vessels.

DOI： 10.1371/journal.pcbi.1008398

Tubulin carboxypeptidase activity of vasohibin-1 inhibits angiogenesis by interfering with endocytosis and trafficking of pro-angiogenic factor receptors. Reviewed International journal

Miho Kobayashi, Ikumi Wakabayashi, Yasuhiro Suzuki, Kashio Fujiwara, Masanori Nakayama, Tetsuro Watabe, Yasufumi Sato

Angiogenesis 24 ( 1 ) 159 - 176 2020.10

Language：English Publishing type：Research paper (scientific journal)

Receptor endocytosis is crucial for integrating extracellular stimuli of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), into the cell via signal transduction. VEGF not only triggers various angiogenic events including endothelial cell (EC) migration, but also induces the expression of negative regulators of angiogenesis, including vasohibin-1 (VASH1). While we have previously reported that VASH1 inhibits angiogenesis in vitro and in vivo, its mode of action on EC behavior remains elusive. Recently VASH1 was shown to have tubulin carboxypeptidase (TCP) activity, mediating the post-translational modification of microtubules (MTs) by detyrosination of α-tubulin within cells. However, the role of VASH1 TCP activity in angiogenesis has not yet been clarified. Here, we showed that VASH1 detyrosinated α-tubulin in ECs and suppressed in vitro and in vivo angiogenesis. In cultured ECs, VASH1 impaired endocytosis and trafficking of VEGF receptor 2 (VEGFR2), which resulted in the decreased signal transduction and EC migration. These effects of VASH1 could be restored by tubulin tyrosine ligase (TTL) in ECs, suggesting that detyrosination of α-tubulin negatively regulates angiogenesis. Furthermore, we found that detyrosinated tubulin-rich MTs were not adequate as trafficking rails for VEGFR2 endocytosis. Consistent with these results, inhibition of TCP activity of VASH1 led to the inhibition of VASH1-mediated suppression of VEGF-induced signals, EC migration, and in vivo angiogenesis. Our results indicate a novel mechanism of VASH1-mediated inhibition of pro-angiogenic factor receptor trafficking via modification of MTs.

DOI： 10.1007/s10456-020-09754-6

The mitochondrial outer membrane protein SYNJ2BP interacts with the cell adhesion molecule TMIGD1 and can recruit it to mitochondria. International journal

Christian Hartmann, Ysabel Alessa Schwietzer, Daniel Kummer, Nils Kirschnick, Esther Hoppe, Eva-Maria Thüring, Mark Glaesner-Ebnet, Frauke Brinkmann, Volker Gerke, Stefan Reuter, Masanori Nakayama, Klaus Ebnet

BMC molecular and cell biology 21 ( 1 ) 30 - 30 2020.4

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is a recently identified cell adhesion molecule which is predominantly expressed by epithelial cells of the intestine and the kidney. Its expression is downregulated in both colon and renal cancer suggesting a tumor suppressive activity. The function of TMIGD1 at the cellular level is largely unclear. Published work suggests a protective role of TMIGD1 during oxidative stress in kidney epithelial cells, but the underlying molecular mechanisms are unknown. RESULTS: In this study, we address the subcellular localization of TMIGD1 in renal epithelial cells and identify a cytoplasmic scaffold protein as interaction partner of TMIGD1. We find that TMIGD1 localizes to different compartments in renal epithelial cells and that this localization is regulated by cell confluency. Whereas it localizes to mitochondria in subconfluent cells it is localized at cell-cell contacts in confluent cells. We find that cell-cell contact localization is regulated by N-glycosylation and that both the extracellular and the cytoplasmic domain contribute to this localization. We identify Synaptojanin 2-binding protein (SYNJ2BP), a PDZ domain-containing cytoplasmic protein, which localizes to both mitochondria and the plasma membrane, as interaction partner of TMIGD1. The interaction of TMIGD1 and SYNJ2BP is mediated by the PDZ domain of SYNJ2BP and the C-terminal PDZ domain-binding motif of TMIGD1. We also find that SYNJ2BP can actively recruit TMIGD1 to mitochondria providing a potential mechanism for the localization of TMIGD1 at mitochondria. CONCLUSIONS: This study describes TMIGD1 as an adhesion receptor that can localize to both mitochondria and cell-cell junctions in renal epithelial cells. It identifies SYNJ2BP as an interaction partner of TMIGD1 providing a potential mechanism underlying the localization of TMIGD1 at mitochondria. The study thus lays the basis for a better understanding of the molecular function of TMIGD1 during oxidative stress regulation.

DOI： 10.1186/s12860-020-00274-1

Does Abatacept Increase Postoperative Adverse Events in Rheumatoid Arthritis Compared with Conventional Synthetic Disease-modifying Drugs? International journal

Hiromu Ito, Shigeyoshi Tsuji, Masanori Nakayama, Yuichi Mochida, Keiichiro Nishida, Hajime Ishikawa, Toshihisa Kojima, Takumi Matsumoto, Ayako Kubota, Takeshi Mochizuki, Koji Sakuraba, Isao Matsushita, Arata Nakajima, Ryota Hara, Akihisa Haraguchi, Tsukasa Matsubara, Katsuaki Kanbe, Natsuko Nakagawa, Masahide Hamaguchi, Shigeki Momohara

The Journal of rheumatology 47 ( 4 ) 502 - 509 2020.4

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: To investigate whether abatacept (ABA) causes more adverse events (AE) than conventional synthetic disease-modifying antirheumatic drugs (csDMARD) after orthopedic surgery in patients with rheumatoid arthritis (RA). METHODS: A retrospective multicenter nested case-control study was performed in 18 institutions. Patients receiving ABA (ABA group) were matched individually with patients receiving csDMARD and/or steroids (control group). Postoperative AE included surgical site infection, delayed wound healing, deep vein thrombosis or pulmonary embolism, flare, and death. The incidence rates of the AE in both groups were compared with the Mantel-Haenszel test. Risk factors for AE were analyzed by logistic regression model. RESULTS: A total of 3358 cases were collected. After inclusion and exclusion, 2651 patients were selected for matching, and 194 patients in 97 pairs were chosen for subsequent comparative analyses between the ABA and control groups. No between-group differences were detected in the incidence rates of each AE or in the incidence rates of total AE (control vs ABA: 15.5% vs 20.7% in total, 5.2% vs 3.1% in death). CONCLUSION: Compared with csDMARD and/or steroids without ABA, adding ABA to the treatment does not appear to increase the incidence rates of postoperative AE in patients with RA undergoing orthopedic surgery. Large cohort studies should be performed to add evidence for the perioperative safety profile of ABA.

DOI： 10.3899/jrheum.181100

Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome. Reviewed International journal

Mengnan Li, Shin-Ya Nishio, Chie Naruse, Meghan Riddell, Sabrina Sapski, Tatsuya Katsuno, Takao Hikita, Fatemeh Mizapourshafiyi, Fiona M Smith, Leanne T Cooper, Min Goo Lee, Masahide Asano, Thomas Boettger, Marcus Krueger, Astrid Wietelmann, Johannes Graumann, Bryan W Day, Andrew W Boyd, Stefan Offermanns, Shin-Ichiro Kitajiri, Shin-Ichi Usami, Masanori Nakayama

Nature communications 11 ( 1 ) 1343 - 1343 2020.3

Language：English Publishing type：Research paper (scientific journal)

Enlarged vestibular aqueduct (EVA) is one of the most commonly identified inner ear malformations in hearing loss patients including Pendred syndrome. While biallelic mutations of the SLC26A4 gene, encoding pendrin, causes non-syndromic hearing loss with EVA or Pendred syndrome, a considerable number of patients appear to carry mono-allelic mutation. This suggests faulty pendrin regulatory machinery results in hearing loss. Here we identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4. EphA2 forms a protein complex with pendrin controlling pendrin localization, which is disrupted in some pathogenic forms of pendrin. Moreover, point mutations leading to amino acid substitution in the EPHA2 gene are identified from patients bearing mono-allelic mutation of SLC26A4. Ephrin-B2 binds to EphA2 triggering internalization with pendrin inducing EphA2 autophosphorylation weakly. The identified EphA2 mutants attenuate ephrin-B2- but not ephrin-A1-induced EphA2 internalization with pendrin. Our results uncover an unexpected role of the Eph/ephrin system in epithelial function.

DOI： 10.1038/s41467-020-15198-9

Regulation of programmed cell death ligand 1 expression by atypical protein kinase C lambda/iota in cutaneous angiosarcoma. Reviewed International journal

Ai Kawamura, Takuji Kawamura, Meghan Riddell, Takao Hikita, Teruki Yanagi, Hiroshi Umemura, Masanori Nakayama

Cancer science 110 ( 5 ) 1780 - 1789 2019.5

Language：English Publishing type：Research paper (scientific journal)

The expression of immune checkpoint proteins such as programmed cell death protein 1 (PD-1) and its ligand (PD-L1) has been shown to correlate with patient prognosis in many malignant cancers. The expression of PD-L1 is controlled by c-Myc; however, further upstream regulation of PD-L1 expression is largely unknown. We have previously shown that atypical protein kinase C lambda/iota (aPKCλ) phosphorylates the Forkhead box protein O1 (FoxO1) transcription factor at Ser218 to suppress its DNA-binding ability, thereby regulating c-Myc expression and controlling physiologic and pathologic endothelial proliferation. The presence of phosphorylation of FoxO1 at Ser218 (pSer218 FoxO1) in cutaneous angiosarcoma (CAS) strongly correlates with poor patient prognosis. Here, we reported that patients with PD-L1+ cells in CAS lesions showed significantly worse prognosis compared to those that were PD-L1- . Expression of PD-L1 correlated with that of aPKCλ or the presence of pSer218FoxO1. Moreover, suppression of aPKCλ expression or inhibition of its activity in HUVECs or AS-M, an established human angiosarcoma cell line, resulted in decreased PD-L1 expression. Our results suggest that combined treatment with immune checkpoint inhibitors and aPKCλ inhibitors could be a novel treatment strategy for CAS patients.

DOI： 10.1111/cas.13981

aPKC controls endothelial growth by modulating c-Myc via FoxO1 DNA-binding ability. Reviewed International journal

Meghan Riddell, Akiko Nakayama, Takao Hikita, Fatemeh Mirzapourshafiyi, Takuji Kawamura, Ayesha Pasha, Mengnan Li, Mikio Masuzawa, Mario Looso, Tim Steinbacher, Klaus Ebnet, Michael Potente, Tomonori Hirose, Shigeo Ohno, Ingrid Fleming, Stefan Gattenlöhner, Phyu P Aung, Thuy Phung, Osamu Yamasaki, Teruki Yanagi, Hiroshi Umemura, Masanori Nakayama

Nature communications 9 ( 1 ) 5357 - 5357 2018.12

Language：English Publishing type：Research paper (scientific journal)

Strict regulation of proliferation is vital for development, whereas unregulated cell proliferation is a fundamental characteristic of cancer. The polarity protein atypical protein kinase C lambda/iota (aPKCλ) is associated with cell proliferation through unknown mechanisms. In endothelial cells, suppression of aPKCλ impairs proliferation despite hyperactivated mitogenic signaling. Here we show that aPKCλ phosphorylates the DNA binding domain of forkhead box O1 (FoxO1) transcription factor, a gatekeeper of endothelial growth. Although mitogenic signaling excludes FoxO1 from the nucleus, consequently increasing c-Myc abundance and proliferation, aPKCλ controls c-Myc expression via FoxO1/miR-34c signaling without affecting its localization. We find this pathway is strongly activated in the malignant vascular sarcoma, angiosarcoma, and aPKC inhibition reduces c-Myc expression and proliferation of angiosarcoma cells. Moreover, FoxO1 phosphorylation at Ser218 and aPKC expression correlates with poor patient prognosis. Our findings may provide a potential therapeutic strategy for treatment of malignant cancers, like angiosarcoma.

DOI： 10.1038/s41467-018-07739-0

PAR-3 controls endothelial planar polarity and vascular inflammation under laminar flow. Reviewed International journal

Takao Hikita, Fatemeh Mirzapourshafiyi, Pedro Barbacena, Meghan Riddell, Ayesha Pasha, Mengnan Li, Takuji Kawamura, Ralf P Brandes, Tomonori Hirose, Shigeo Ohno, Holger Gerhardt, Michiyuki Matsuda, Claudio A Franco, Masanori Nakayama

EMBO reports 19 ( 9 ) 2018.9

Language：English Publishing type：Research paper (scientific journal)

Impaired cell polarity is a hallmark of diseased tissue. In the cardiovascular system, laminar blood flow induces endothelial planar cell polarity, represented by elongated cell shape and asymmetric distribution of intracellular organelles along the axis of blood flow. Disrupted endothelial planar polarity is considered to be pro-inflammatory, suggesting that the establishment of endothelial polarity elicits an anti-inflammatory response. However, a causative relationship between polarity and inflammatory responses has not been firmly established. Here, we find that a cell polarity protein, PAR-3, is an essential gatekeeper of GSK3β activity in response to laminar blood flow. We show that flow-induced spatial distribution of PAR-3/aPKCλ and aPKCλ/GSK3β complexes controls local GSK3β activity and thereby regulates endothelial planar polarity. The spatial information for GSK3β activation is essential for flow-dependent polarity to the flow axis, but is not necessary for flow-induced anti-inflammatory response. Our results shed light on a novel relationship between endothelial polarity and vascular homeostasis highlighting avenues for novel therapeutic strategies.

DOI： 10.15252/embr.201745253

Regulation of cell polarity by cell adhesion receptors. International journal

Klaus Ebnet, Daniel Kummer, Tim Steinbacher, Amrita Singh, Masanori Nakayama, Maja Matis

Seminars in cell & developmental biology 81 2 - 12 2018.9

Language：English Publishing type：Research paper (scientific journal)

The ability of cells to polarize is an intrinsic property of almost all cells and is required for the devlopment of most multicellular organisms. To develop cell polarity, cells integrate various signals derived from intrinsic as well as extrinsic sources. In the recent years, cell-cell adhesion receptors have turned out as important regulators of cellular polarization. By interacting with conserved cell polarity proteins, they regulate the recruitment of polarity complexes to specific sites of cell-cell adhesion. By initiating intracellular signaling cascades at those sites, they trigger their specific subcellular activation. Not surprisingly, cell-cell adhesion receptors regulate diverse aspects of cell polarity, including apico-basal polarity in epithelial and endothelial cells, front-to-rear polarity in collectively migrating cells, and planar cell polarity during organ development. Here, we review the recent developments highlighting the central roles of cell-cell adhesion molecules in the development of cell polarity.

DOI： 10.1016/j.semcdb.2017.07.032

Pericytes regulate VEGF-induced endothelial sprouting through VEGFR1. Reviewed International journal

Hanna M Eilken, Rodrigo Diéguez-Hurtado, Inga Schmidt, Masanori Nakayama, Hyun-Woo Jeong, Hendrik Arf, Susanne Adams, Napoleone Ferrara, Ralf H Adams

Nature communications 8 ( 1 ) 1574 - 1574 2017.11

Language：English Publishing type：Research paper (scientific journal)

Pericytes adhere to the abluminal surface of endothelial tubules and are required for the formation of stable vascular networks. Defective endothelial cell-pericyte interactions are frequently observed in diseases characterized by compromised vascular integrity such as diabetic retinopathy. Many functional properties of pericytes and their exact role in the regulation of angiogenic blood vessel growth remain elusive. Here we show that pericytes promote endothelial sprouting in the postnatal retinal vasculature. Using genetic and pharmacological approaches, we show that the expression of vascular endothelial growth factor receptor 1 (VEGFR1) by pericytes spatially restricts VEGF signalling. Angiogenic defects caused by pericyte depletion are phenocopied by intraocular injection of VEGF-A or pericyte-specific inactivation of the murine gene encoding VEGFR1. Our findings establish that pericytes promote endothelial sprouting, which results in the loss of side branches and the enlargement of vessels when pericyte function is impaired or lost.

DOI： 10.1038/s41467-017-01738-3

VE-cadherin interacts with cell polarity protein Pals1 to regulate vascular lumen formation. International journal

Benjamin F Brinkmann, Tim Steinbacher, Christian Hartmann, Daniel Kummer, Denise Pajonczyk, Fatemeh Mirzapourshafiyi, Masanori Nakayama, Thomas Weide, Volker Gerke, Klaus Ebnet

Molecular biology of the cell 27 ( 18 ) 2811 - 21 2016.9

Language：English Publishing type：Research paper (scientific journal)

Blood vessel tubulogenesis requires the formation of stable cell-to-cell contacts and the establishment of apicobasal polarity of vascular endothelial cells. Cell polarity is regulated by highly conserved cell polarity protein complexes such as the Par3-aPKC-Par6 complex and the CRB3-Pals1-PATJ complex, which are expressed by many different cell types and regulate various aspects of cell polarity. Here we describe a functional interaction of VE-cadherin with the cell polarity protein Pals1. Pals1 directly interacts with VE-cadherin through a membrane-proximal motif in the cytoplasmic domain of VE-cadherin. VE-cadherin clusters Pals1 at cell-cell junctions. Mutating the Pals1-binding motif in VE-cadherin abrogates the ability of VE-cadherin to regulate apicobasal polarity and vascular lumen formation. In a similar way, deletion of the Par3-binding motif at the C-terminus of VE-cadherin impairs apicobasal polarity and vascular lumen formation. Our findings indicate that the biological activity of VE-cadherin in regulating endothelial polarity and vascular lumen formation is mediated through its interaction with the two cell polarity proteins Pals1 and Par3.

DOI： 10.1091/mbc.E16-02-0127

Regulation of vascular endothelial growth factor receptor function in angiogenesis by numb and numb-like. Reviewed International journal

Max van Lessen, Masanori Nakayama, Katsuhiro Kato, Jung Mo Kim, Kozo Kaibuchi, Ralf H Adams

Arteriosclerosis, thrombosis, and vascular biology 35 ( 8 ) 1815 - 25 2015.8

Language：English Publishing type：Research paper (scientific journal)

OBJECTIVE: Vascular endothelial growth factor (VEGF) signaling is a major regulator of physiological and pathological angiogenesis. VEGF receptor activity is strongly controlled by endocytosis, which can terminate or enhance signal transduction in the angiogenic endothelium, but the exact molecular regulation of these processes remains incompletely understood. We have therefore examined the function of Numb family clathrin-associated sorting proteins in angiogenesis. APPROACH AND RESULTS: We show that Numb proteins are expressed by endothelial cells during retinal angiogenesis in mice. Inducible inactivation of the Numb/Numbl genes in the postnatal endothelium led to impaired vessel growth, reduced endothelial proliferation and sprouting, and decreased VEGF receptor activation. Biochemistry and cell biology experiments established that Numb can interact with VEGFR2 and VEGFR3 and controls VEGF receptor activation in response to ligand stimulation. Experiments in cultured endothelial cells showed that Numb proteins counteract VEGF receptor degradation and promote VEGFR2 recycling back to the plasma membrane. CONCLUSIONS: Numb proteins control VEGF receptor endocytosis, signaling, and recycling in endothelial cells, which promotes the angiogenic growth of blood vessels.

DOI： 10.1161/ATVBAHA.115.305473

Integrin β1 controls VE-cadherin localization and blood vessel stability. Reviewed International journal

Hiroyuki Yamamoto, Manuel Ehling, Katsuhiro Kato, Kenichi Kanai, Max van Lessen, Maike Frye, Dagmar Zeuschner, Masanori Nakayama, Dietmar Vestweber, Ralf H Adams

Nature communications 6 6429 - 6429 2015.3

Language：English Publishing type：Research paper (scientific journal)

Angiogenic blood vessel growth requires several distinct but integrated cellular activities. Endothelial cell sprouting and proliferation lead to the expansion of the vasculature and give rise to a highly branched, immature plexus, which is subsequently reorganized into a mature and stable network. Although it is known that integrin-mediated cell-matrix interactions are indispensable for embryonic angiogenesis, little is known about the function of integrins in different steps of vascular morphogenesis. Here, by investigating the integrin β1-subunit with inducible and endothelial-specific gene targeting in the postnatal mouse retina, we show that β1 integrin promotes endothelial sprouting but is a negative regulator of proliferation. In maturing vessels, integrin β1 is indispensable for proper localization of VE-cadherin and thereby cell-cell junction integrity. The sum of our findings establishes that integrin β1 has critical functions in the growing and maturing vasculature, and is required for the formation of stable, non-leaky blood vessels.

DOI： 10.1038/ncomms7429

Ephrin-B2 controls PDGFRβ internalization and signaling. Reviewed International journal

Akiko Nakayama, Masanori Nakayama, Christopher J Turner, Susanne Höing, John J Lepore, Ralf H Adams

Genes & development 27 ( 23 ) 2576 - 89 2013.12

Language：English Publishing type：Research paper (scientific journal)

B-class ephrins, ligands for EphB receptor tyrosine kinases, are critical regulators of growth and patterning processes in many organs and species. In the endothelium of the developing vasculature, ephrin-B2 controls endothelial sprouting and proliferation, which has been linked to vascular endothelial growth factor (VEGF) receptor endocytosis and signaling. Ephrin-B2 also has essential roles in supporting mural cells (namely, pericytes and vascular smooth muscle cells [VSMCs]), but the underlying mechanism is not understood. Here, we show that ephrin-B2 controls platelet-derived growth factor receptor β (PDGFRβ) distribution in the VSMC plasma membrane, endocytosis, and signaling in a fashion that is highly distinct from its role in the endothelium. Absence of ephrin-B2 in cultured VSMCs led to the redistribution of PDGFRβ from caveolin-positive to clathrin-associated membrane fractions, enhanced PDGF-B-induced PDGFRβ internalization, and augmented downstream mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK) activation but impaired Tiam1-Rac1 signaling and proliferation. Accordingly, mutant mice lacking ephrin-B2 expression in vascular smooth muscle developed vessel wall defects and aortic aneurysms, which were associated with impaired Tiam1 expression and excessive activation of MAP kinase and JNK. Our results establish that ephrin-B2 is an important regulator of PDGFRβ endocytosis and thereby acts as a molecular switch controlling the downstream signaling activity of this receptor in mural cells.

DOI： 10.1101/gad.224089.113

Coordination of VEGF receptor trafficking and signaling by coreceptors. Reviewed International journal

Masanori Nakayama, Philipp Berger

Experimental cell research 319 ( 9 ) 1340 - 7 2013.5

Language：English Publishing type：Research paper (scientific journal)

During development, regeneration and in certain pathological settings, the vasculature is expanded and remodeled substantially. Proper morphogenesis and function of blood vessels are essential in multicellular organisms. Upon stimulation with growth factors including vascular endothelial growth factors (VEGFs), the activation, internalization and sorting of receptor tyrosine kinases (RTKs) orchestrate developmental processes and the homeostatic maintenance of all organs including the vasculature. Previously, RTK signaling was thought to occur exclusively at the plasma membrane, a process that was subsequently terminated by endocytosis and receptor degradation. However, this model turned out to be an oversimplification and there is now a substantial amount of reports indicating that receptor internalization and trafficking to intracellular compartments depends on coreceptors leading to the activation of specific signaling pathways. Here we review the latest findings concerning endocytosis and intracellular trafficking of VEGFRs. The body of evidence is compelling that VEGF receptor trafficking is coordinated with other proteins such as Neuropilin-1, ephrin-B2, VE-cadherin and protein phosphatases.

DOI： 10.1016/j.yexcr.2013.03.008

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