菊池 章 and Shinji Matsumoto : Hippoシグナル:サイトカイン・増殖因子キーワード事典, 羊土社, 2015.
4.
Akira Kikuchi, Shinji Matsumoto, Katsumi Fumoto and Akira Sato : Modulation of Wnt Signaling by Endocytosis of Receptor Complexes, John Wiley & Sons, Inc., 2014.
(Summary)
Summary Current evidence suggests that in addition to the specific combination of Wnt ligands and receptors, endocytosis of the Wnt-receptor complex, binding of Wnt to heparan sulfate proteoglycans (HSPGs), and ubiquitination of Wnt receptors are involved in the regulation of the Wnt signaling pathway. This chapter highlights new insight into the mechanisms of Wnt signaling pathway activation, which occurs on and inside the cell surface membrane. There are two different types of endocytosis, clathrin-mediated endocytosis and caveolin-mediated endocytosis. Clathrin and caveolin play a major role in the respective pathways. Compared with the controversial roles of endocytic pathways in the β-catenin-dependent pathway, the importance of endocytosis in the β-catenin-independent pathway is well documented.
5.
菊池 章 and Shinji Matsumoto : 細胞増殖・運動・死とがん:プログレッシブ 生命科学, 南山堂, 2014.
6.
菊池 章 and Shinji Matsumoto : Wntシグナル:がん生物学イラストレイテッド 第1版, 羊土社, 2011.
Academic Paper (Judged Full Paper):
1.
Hideki Yamamoto, Ryota Sada, Akikazu Harada, Shinji Matsumoto and Akira Kikuchi : Annexin A2 mediates plasma membrane localization of CKAP4, a dickkopf1 receptor, in cancer cells., Journal of Cell Science, Vol.in press, 2024.
2.
Ryota Sada, Hideki Yamamoto, Shinji Matsumoto, Akikazu Harada and Akira Kikuchi : Newly developed humanized anti-CKAP4 antibody suppresses pancreatic cancer growth by inhibiting DKK1-CKAP4 signaling., Cancer Science, Vol.115, No.10, 3358-3369, 2024.
(Summary)
Cytoskeleton-associated protein 4 (CKAP4) is a cell surface receptor for Dickkopf 1 (DKK1), a secreted protein. The DKK1-CKAP4 pathway is activated in various malignant tumors, including pancreatic, lung, esophageal, and liver cancers, to promote tumor growth. Thus, CKAP4 has been expected to represent a novel molecular target of cancer therapy. Recombinant mouse anti-CKAP4 antibodies were generated based on an original mouse antibody (3F11-2B10) and inhibited DKK1-CKAP4 signaling and xenograft tumor formation induced by pancreatic cancer cells, which was comparable with 3F11-2B10. From the 3F11-2B10 nucleotide sequence, humanized anti-CKAP4 antibody (Hv1Lt1) was subsequently developed. The binding affinity of Hv1Lt1 for CKAP4 was superior to that of 3F11-2B10. Hv1Lt1 inhibited DKK1 binding to CKAP4, AKT activity, and sphere formation of pancreatic cancer cells, which was comparable with 3F11-2B10. Hv1Lt1 also suppressed xenograft tumor formation induced by human pancreatic cancer cells and tumor growth in murine cancer models, in which murine pancreatic cancer organoids were orthotopically transplanted into the pancreas. In resected tumor samples from mice treated with Hv1Lt1, anti-tumor immune reactions were modulated and cytotoxic T cells were highly infiltrated in the tumor microenvironment. Additionally, combination of Hv1Lt1 and other chemotherapy drugs exhibited stronger effects compared with monotherapy. These results suggest that Hv1Lt1 represents a promising anti-cancer therapy.
Koei Shinzawa, Shinji Matsumoto, Ryota Sada, Akikazu Harada, Kaori Saitoh, Keiko Kato, Satsuki Ikeda, Akiyoshi Hirayama, Kazunori Yokoi, Atsushi Tanemura, Keisuke Nimura, Masahito Ikawa, Tomoyoshi Soga and Akira Kikuchi : GREB1 isoform 4 is specifically transcribed by MITF and required for melanoma proliferation., Oncogene, Vol.42, No.42, 3142-3156, 2023.
(Summary)
Growth regulation by estrogen in breast cancer 1 (GREB1) is involved in hormone-dependent and -independent tumor development (e.g., hepatoblastoma). In this study, we found that a GREB1 splicing variant, isoform 4 (Is4), which encodes C-terminal half of full-length GREB1, is specifically expressed via microphthalmia-associated transcription factor (MITF) in melanocytic melanoma, and that two MITF-binding E-box CANNTG motifs at the 5'-upstream region of GREB1 exon 19 are necessary for GREB1 Is4 transcription. MITF and GREB1 Is4 were strongly co-expressed in approximately 20% of the melanoma specimens evaluated (17/89 cases) and their expression was associated with tumor thickness. GREB1 Is4 silencing reduced melanoma cell proliferation in association with altered expression of cell proliferation-related genes in vitro. In addition, GREB1 Is4 targeting by antisense oligonucleotide (ASO) decreased melanoma xenograft tumor formation and GREB1 Is4 expression in a BRAF; PTEN melanoma mouse model promoted melanoma formation, demonstrating the crucial role of GREB1 Is4 for melanoma proliferation in vivo. GREB1 Is4 bound to CAD, the rate-limiting enzyme of pyrimidine metabolism, and metabolic flux analysis revealed that GREBI Is4 is necessary for pyrimidine synthesis. These results suggest that MITF-dependent GREB1 Is4 expression leads to melanoma proliferation and GREB1 Is4 represents a new molecular target in melanoma.
Shinji Matsumoto, Akikazu Harada, Minami Seta, Masayuki Akita, Hidetoshi Gon, Takumi Fukumoto and Akira Kikuchi : Wnt Signaling Stimulates Cooperation between GREB1 and HNF4α to Promote Proliferation in Hepatocellular Carcinoma., Cancer Research, Vol.83, No.14, 2312-2327, 2023.
(Summary)
GREB1 is a liver cancer-specific Wnt signaling target gene that induces an oncogenic shift of HNF4α, a putative tumor suppressor, and may represent a therapeutic target in Wnt-activated hepatocellular carcinoma.
These results collectively suggest that Wnt5a-YAP signaling axis mediates mechanotransduction in cardiomyocytes and contributes to heart failure progression.
Kosuke Iguchi, Ryota Sada, Shinji Matsumoto, Hirokazu Kimura, Yoh Zen, Masayuki Akita, Hidetoshi Gon, Takumi Fukumoto and Akira Kikuchi : DKK1-CKAP4 signal axis promotes hepatocellular carcinoma aggressiveness., Cancer Science, Vol.114, No.5, 2063-2077, 2023.
(Summary)
Hepatocellular carcinoma (HCC) is the most prevalent malignant liver neoplasm. Despite the advances in diagnosis and treatment, the prognosis of HCC patients remains poor. Cytoskeleton-associated membrane protein 4 (CKAP4) is a receptor of the glycosylated secretory protein Dickkopf-1 (DKK1), and the DKK1-CKAP4 axis is activated in pancreatic, lung, and esophageal cancer cells. Expression of DKK1 and CKAP4 has been examined in HCC in independent studies that yielded contradictory results. In this study, the relationship between the DKK1-CKAP4 axis and HCC was comprehensively examined. In 412 HCC cases, patients whose tumors were positive for both DKK1 and CKAP4 had a poor prognosis compared to those who were positive for only one of these markers or negative for both. Deletion of either DKK1 or CKAP4 inhibited HCC cell growth. In contrast to WT DKK1, DKK1 lacking the CKAP4 binding region did not rescue the phenotypes caused by DKK1 depletion, suggesting that binding of DKK1 to CKAP4 is required for HCC cell proliferation. Anti-CKAP4 Ab inhibited HCC growth, and its antitumor effect was clearly enhanced when combined with lenvatinib, a multikinase inhibitor. These results indicate that simultaneous expression of DKK1 and CKAP4 is involved in the aggressiveness of HCC, and that the combination of anti-CKAP4 Ab and other therapeutics including lenvatinib could represent a promising strategy for treating advanced HCC.
Akikazu Harada, Shinji Matsumoto, Yoshiaki Yasumizu, Kensaku Shojima, Toshiyuki Akama, Hidetoshi Eguchi and Akira Kikuchi : Localization of KRAS downstream target ARL4C to invasive pseudopods accelerates pancreatic cancer cell invasion., eLife, Vol.10, e66721, 2021.
(Summary)
Pancreatic cancer has a high mortality rate due to metastasis. Whereas KRAS is mutated in most pancreatic cancer patients, controlling KRAS or its downstream effectors has not been succeeded clinically. ARL4C is a small G protein whose expression is induced by the Wnt and EGF-RAS pathways. In the present study, we found that ARL4C is frequently overexpressed in pancreatic cancer patients and showed that its localization to invasive pseudopods is required for cancer cell invasion. IQGAP1 was identified as a novel interacting protein for ARL4C. ARL4C recruited IQGAP1 and its downstream effector, MMP14, to invasive pseudopods. Specific localization of ARL4C, IQGAP1, and MMP14 was the active site of invasion, which induced degradation of the extracellular matrix. Moreover, subcutaneously injected antisense oligonucleotide against ARL4C into tumor-bearing mice suppressed metastasis of pancreatic cancer. These results suggest that ARL4C-IQGAP1-MMP14 signaling is activated at invasive pseudopods of pancreatic cancer cells.
Yosuke Miyachi, Miki Nishio, Junji Otani, Shinji Matsumoto, Akira Kikuchi, Wah Tak Mak, Tomohiko Maehama and Akira Suzuki : TAZ inhibits acinar cell differentiation but promotes immature ductal cell proliferation in adult mouse salivary glands., Genes to Cells, Vol.26, No.9, 714-726, 2021.
(Summary)
There are currently no treatments for salivary gland diseases, making it vital to understand signaling mechanisms operating in acinar and ductal cells so as to develop regenerative therapies. To date, little work has focused on elucidating the signaling cascades controlling the differentiation of these cell types in adult mammals. To analyze the function of the Hippo-TAZ/YAP1 pathway in adult mouse salivary glands, we generated adMOB1DKO mice in which both MOB1A and MOB1B were TAM-inducibly deleted when the animals were adults. Three weeks after TAM treatment, adMOB1DKO mice exhibited smaller submandibular glands (SMGs) than controls with a decreased number of acinar cells and an increased number of immature dysplastic ductal cells. The mutants suffered from reduced saliva production accompanied by mild inflammatory cell infiltration and fibrosis in SMGs, similar to the Sjogren's syndrome. MOB1-deficient acinar cells showed normal proliferation and apoptosis but decreased differentiation, leading to an increase in acinar/ductal bilineage progenitor cells. These changes were TAZ-dependent but YAP1-independent. Biochemically, MOB1-deficient salivary epithelial cells showed activation of the TAZ/YAP1 and β-catenin in ductal cells, but reduced SOX2 and SOX10 expression in acinar cells. Thus, Hippo-TAZ signaling is critical for proper ductal and acinar cell differentiation and function in adult mice.
Takeshi Harada, Ryota Sada, Yoshito Osugi, Shinji Matsumoto, Tomoki Matsuda, Mitsuko Hayashi-Nishino, Takeharu Nagai, Akihiro Harada and Akira Kikuchi : Palmitoylated CKAP4 regulates mitochondrial functions through an interaction with VDAC2 at ER-mitochondria contact sites., Journal of Cell Science, Vol.133, No.21, jcs249045, 2020.
(Summary)
Cytoskeleton-associated protein 4 (CKAP4) is a palmitoylated type II transmembrane protein localized to the endoplasmic reticulum (ER). Here, we found that knockout (KO) of CKAP4 in HeLaS3 cells induces the alteration of mitochondrial structures and increases the number of ER-mitochondria contact sites. To understand the involvement of CKAP4 in mitochondrial functions, the binding proteins of CKAP4 were explored, enabling identification of the mitochondrial porin voltage-dependent anion-selective channel protein 2 (VDAC2), which is localized to the outer mitochondrial membrane. Palmitoylation at Cys of CKAP4 was required for the binding between CKAP4 and VDAC2. In CKAP4 KO cells, the binding of inositol trisphosphate receptor (IP3R) and VDAC2 was enhanced, the intramitochondrial Ca concentration increased and the mitochondrial membrane potential decreased. In addition, CKAP4 KO decreased the oxidative consumption rate, cancer cell proliferation under low-glucose conditions and xenograft tumor formation. The phenotypes were not rescued by expression of a palmitoylation-deficient CKAP4 mutant. These results suggest that CKAP4 plays a role in maintaining mitochondrial functions through the binding to VDAC2 at ER-mitochondria contact sites and that palmitoylation is required for this novel function of CKAP4.This article has an associated First Person interview with the first author of the paper.
Kenji Kimura, Shinji Matsumoto, Takeshi Harada, Eiichi Morii, Izumi Nagatomo, Yasushi Shintani and Akira Kikuchi : ARL4C is associated with initiation and progression of lung adenocarcinoma and represents a therapeutic target., Cancer Science, Vol.111, No.3, 951-961, 2020.
(Summary)
Lung adenocarcinoma is the most common histological type of lung cancer and is classified into adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA). Atypical adenomatous hyperplasia (AAH) lesions are possible precursors to adenocarcinoma. However, the mechanism underlying the stepwise continuum of lung adenocarcinoma is unclear. In this study, the involvement of ADP-ribosylation factor (ARF)-like (ARL) 4C (ARL4C), a member of the small GTP-binding protein family, in the progression of lung adenocarcinoma and the possibility of ARL4C as a molecular target for lung cancer therapy were explored. ARL4C was frequently expressed in AAH and ARL4C expression in immortalized human small airway epithelial cells promoted cell proliferation and suppressed cell death. In addition, ARL4C was expressed with increased frequency in AIS, MIA and IA in a stage-dependent manner, and the expression was correlated with histologic grade, fluorine-18 fluorodeoxyglucose uptake and poor prognosis. An anti-sense oligonucleotide (ASO) against ARL4C (ARL4C ASO-1316) inhibited RAS-related C3 botulinum toxin substrate activity and nuclear import of Yes-associated protein and transcriptional coactivator with PDZ-binding motif, and suppressed in vitro proliferation and migration of lung cancer cells with KRAS or epidermal growth factor receptor (EGFR) mutations. In addition, transbronchial administration of ARL4C ASO-1316 suppressed orthotopic tumor formation induced by these cancer cells. Thus, ARL4C is involved in the initiation of the premalignant stage and is associated with the stepwise continuum of lung adenocarcinoma. ARL4C ASO-1316 would be useful for lung adenocarcinoma patients expressing ARL4C regardless of the KRAS or EGFR mutation.
Shinji Matsumoto, Taku Yamamichi, Koei Shinzawa, Yuuya Kasahara, Satoshi Nojima, Takahiro Kodama, Satoshi Obika, Tetsuo Takehara, Eiichi Morii, Hiroomi Okuyama and Akira Kikuchi : GREB1 induced by Wnt signaling promotes development of hepatoblastoma by suppressing TGFβ signaling., Nature Communications, Vol.10, No.1, 3882, 2019.
(Summary)
The β-catenin mutation is frequently observed in hepatoblastoma (HB), but the underlying mechanism by which Wnt/β-catenin signaling induces HB tumor formation is unknown. Here we show that expression of growth regulation by estrogen in breast cancer 1 (GREB1) depends on Wnt/β-catenin signaling in HB patients. GREB1 is localized to the nucleus where it binds Smad2/3 in a competitive manner with p300 and inhibits TGFβ signaling, thereby promoting HepG2 HB cell proliferation. Forced expression of β-catenin, YAP, and c-Met induces HB-like mouse liver tumor (BYM mice), with an increase in GREB1 expression and HB markers. Depletion of GREB1 strongly suppresses marker gene expression and HB-like liver tumorigenesis, and instead enhances TGFβ signaling in BYM mice. Furthermore, antisense oligonucleotides for GREB1 suppress the formation of HepG2 cell-induced tumors and HB-like tumors in vivo. We propose that GREB1 is a target molecule of Wnt/β-catenin signaling and required for HB progression.
Shinsuke Fujii, Kengo Nagata, Shinji Matsumoto, Ken-Ichi Kohashi, Akira Kikuchi, Yoshinao Oda, Tamotsu Kiyoshima and Naohisa Wada : Wnt/β-catenin signaling, which is activated in odontomas, reduces Sema3A expression to regulate odontogenic epithelial cell proliferation and tooth germ development., Scientific Reports, Vol.9, No.1, 4257, 2019.
(Summary)
Odontomas, developmental anomalies of tooth germ, frequently occur in familial adenomatous polyposis patients with activated Wnt/β-catenin signaling. However, roles of Wnt/β-catenin signaling in odontomas or odontogenic cells are unclear. Herein, we investigated β-catenin expression in odontomas and functions of Wnt/β-catenin signaling in tooth germ development. β-catenin frequently accumulated in nucleus and/or cellular cytoplasm of odontogenic epithelial cells in human odontoma specimens, immunohistochemically. Wnt/β-catenin signaling inhibited odontogenic epithelial cell proliferation in both cell line and tooth germ development, while inducing immature epithelial bud formation. We identified Semaphorin 3A (Sema3A) as a downstream molecule of Wnt/β-catenin signaling and showed that Wnt/β-catenin signaling-dependent reduction of Sema3A expression resulted in suppressed odontogenic epithelial cell proliferation. Sema3A expression is required in appropriate epithelial budding morphogenesis. These results suggest that Wnt/β-catenin signaling negatively regulates odontogenic epithelial cell proliferation and tooth germ development through decreased-Sema3A expression, and aberrant activation of Wnt/β-catenin signaling may associate with odontoma formation.
mRNA levels and inhibited the activity of AKT in HCC cells, suggesting that the downstream signaling of ARL4C in HCC cells is different from that in lung and colon cancer cells. In addition, subcutaneous injection of ARL4C ASO was effective in reducing the growth of primary HCC and metastatic colorectal cancer in the liver of immunodeficient mice. ARL4C ASO accumulated in cancer cells more efficiently than the surrounding normal cells in the liver and decreased ARL4C expression in the tumor. These results suggest that ARL4C ASO represents a novel targeted nucleic acid medicine for the treatment of primary and metastatic liver cancers.
Hideki Yamamoto, Daisuke Umeda, Shinji Matsumoto and Akira Kikuchi : LDL switches the LRP6 internalization route from flotillin dependent to clathrin dependent in hepatic cells., Journal of Cell Science, Vol.130, No.20, 3542-3556, 2017.
(Summary)
Low-density lipoprotein (LDL) receptor-related protein 6 (LRP6) was originally identified as a co-receptor of the Wnt signalling pathway and has been shown to be involved in LDL transport. In polarized hepatocytes, many apical proteins are sorted to the basolateral membrane and then internalized and transported to the apical bile canalicular membrane - a process known as transcytosis. We show that LRP6 is transcytosed to the apical membrane of polarized hepatic HepG2 cells via a flotillin-dependent manner in the absence of LDL. LRP6 formed a complex with Niemann-Pick type C1-like 1 (NPC1L1), which is localized to the bile canalicular membrane of the liver and is involved in cholesterol absorption from the bile. LRP6 was required for apical membrane localization of NPC1L1 in the absence of LDL. Clathrin-dependent LRP6 internalization occurred in the presence of LDL, which resulted in trafficking of LRP6 to the lysosome, thereby reducing apical sorting of LRP6 and NPC1L1. These results suggest that LRP6 endocytosis proceeds by two routes, depending on the presence of LDL, and that LRP6 controls the intracellular destination of NPC1L1 in hepatocytes.
(Keyword)
Cell Polarity / Clathrin / Hep G2 Cells / Humans / Lipoproteins, LDL / Low Density Lipoprotein Receptor-Related Protein-6 / Membrane Microdomains / Membrane Proteins / Membrane Transport Proteins / Protein Transport / Transcytosis
Shinsuke Fujii, Keiko Shinjo, Shinji Matsumoto, Takeshi Harada, Satoshi Nojima, Sunao Sato, Yu Usami, Satoru Toyosawa, Eiichi Morii, Yutaka Kondo and Akira Kikuchi : Epigenetic upregulation of ARL4C, due to DNA hypomethylation in the 3'-untranslated region, promotes tumorigenesis of lung squamous cell carcinoma., Oncotarget, Vol.7, No.49, 81571-81587, 2016.
(Summary)
ADP-ribosylation factor (ARF)-like 4c (ARL4C) expression, induced by a combination of Wnt/β-catenin and EGF/Ras signaling, has been demonstrated to form epithelial morphogenesis. ARL4C overexpression, due to Wnt/β-catenin and EGF/Ras signaling alterations, was involved in tumorigenesis. It was also reported that ARL4C expression correlates with DNA hypomethylation in the 3'-untranslated region (UTR) of ARL4C gene during lymphogenesis. The current study was conducted to investigate the expression and functions of ARL4C due to DNA hypomethylation in lung and tongue cancers. Immunohistochemical analyses of tissue specimens obtained from lung and tongue squamous cell carcinoma (SCC) patients revealed that ARL4C is not observed in non-tumor regions, but is strongly expressed at high frequencies in tumor lesions. Although inhibition of Wnt/β-catenin or Ras/MAP kinase signaling did not decrease ARL4C expression in NCI-H520 lung SCC cells, ARL4C DNA was clearly hypomethylated in the 3'-UTR. Ten-eleven translocation methylcytosine dioxygenase (TET) enzyme, which mediates DNA demethylation, was highly expressed in NCI-H520 cells. Knockout of TET family proteins (TET1-3) in NCI-H520 cells reduced 5-hydroxymethylcytosine (5hmC) levels and promoted DNA methylation in the 3'-UTR, leading to the decrease in ARL4C expression and ARL4C-mediated cellular migration. In tumor lesions of ARL4C-positive lung SCC, 5hmC was frequently detected and DNA methylation in the 3'-UTR of ARL4C gene was lower than in non-tumor regions, which were consistent with the Cancer Genome Atlas dataset. These results suggest that ARL4C is expressed due to hypomethylation in the 3'-UTR for certain types of cancers and that ARL4C methylation status is involved in cancer cell function.
(Keyword)
3' Untranslated Regions / 5-Methylcytosine / A549 Cells / ADP-Ribosylation Factors / Adult / Aged / Aged, 80 and over / Carcinoma, Squamous Cell / Cell Movement / Cell Proliferation / DNA Methylation / DNA-Binding Proteins / Dioxygenases / Epigenesis, Genetic / Female / Gene Expression Regulation, Neoplastic / HeLa Cells / Head and Neck Neoplasms / Humans / Lung Neoplasms / Male / Middle Aged / Mixed Function Oxygenases / Neoplasm Invasiveness / Proto-Oncogene Proteins / RNA Interference / Signal Transduction / Squamous Cell Carcinoma of Head and Neck / Time Factors / Tongue Neoplasms / Transfection / Up-Regulation
Cheng Boon Lim, Shinji Matsumoto, Hideki Yamamoto, Hiroki Mizuno, Junichi Kikuta, Masaru Ishii and Akira Kikuchi : Prickle1 promotes focal adhesion disassembly in cooperation with the CLASP-LL5β complex in migrating cells., Journal of Cell Science, Vol.129, No.16, 3115-3129, 2016.
(Summary)
Prickle is known to be involved in planar cell polarity, including convergent extension and cell migration; however, the detailed mechanism by which Prickle regulates cellular functions is not well understood. Here, we show that Prickle1 regulates front-rear polarization and migration of gastric cancer MKN1 cells. Prickle1 preferentially accumulated at the cell retraction site in close proximity to paxillin at focal adhesions. Prickle1 dynamics correlated with those of paxillin during focal adhesion disassembly. Furthermore, Prickle1 was required for focal adhesion disassembly. CLASPs (of which there are two isoforms, CLASP1 and CLASP2, in mammals) and LL5β (also known as PHLDB2) have been reported to form a complex at cell edges and to control microtubule-dependent focal adhesion disassembly. Prickle1 was associated with CLASPs and LL5β, and was required for the LL5β-dependent accumulation of CLASPs at the cell edge. Knockdown of CLASPs and LL5β suppressed Prickle1-dependent cell polarization and migration. Prickle1 localized to the membrane through its farnesyl moiety, and the membrane localization was necessary for Prickle1 to regulate migration, to bind to CLASPs and LL5β, and to promote microtubule targeting of focal adhesions. Taken together, these results suggest that Prickle1 promotes focal adhesion disassembly during the retraction processes of cell polarization and migration.
Shinji Matsumoto, Takayuki Kurimoto, Mark M Taketo, Shinsuke Fujii and Akira Kikuchi : The WNT/MYB pathway suppresses KIT expression to control the timing of salivary proacinar differentiation and duct formation., Development, Vol.143, No.13, 2311-2324, 2016.
(Summary)
Growth factor signaling is involved in the development of various organs, but how signaling regulates organ morphogenesis and differentiation in a coordinated manner remains to be clarified. Here, we show how WNT signaling controls epithelial morphogenetic changes and differentiation using the salivary gland as a model. Experiments using genetically manipulated mice and organ cultures revealed that WNT signaling at an early stage (E12-E15) of submandibular salivary gland (SMG) development inhibits end bud morphogenesis and differentiation into proacini by suppressing Kit expression through the upregulation of the transcription factor MYB, and concomitantly increasing the expression of distal progenitor markers. In addition, WNT signaling at the early stage of SMG development promoted end bud cell proliferation, leading to duct formation. WNT signaling reduction at a late stage (E16-E18) of SMG development promoted end bud maturation and suppressed duct formation. Thus, WNT signaling controls the timing of SMG organogenesis by keeping end bud cells in an undifferentiated bipotent state.
Akira Sato, Hisako Kayama, Kensaku Shojima, Shinji Matsumoto, Hirofumi Koyama, Yasuhiro Minami, Satoshi Nojima, Eiichi Morii, Hiroaki Honda, Kiyoshi Takeda and Akira Kikuchi : The Wnt5a-Ror2 axis promotes the signaling circuit between interleukin-12 and interferon-γ in colitis., Scientific Reports, Vol.5, 10536, 2015.
(Summary)
Wnt5a, which regulates various cellular functions in Wnt signaling, is involved in inflammatory responses, however the mechanism is not well understood. We examined the role of Wnt5a signaling in intestinal immunity using conditional knockout mice for Wnt5a and its receptor Ror2. Removing Wnt5a or Ror2 in adult mice suppressed dextran sodium sulfate (DSS)-induced colitis. It also attenuated the DSS-dependent increase in inflammatory cytokine production and decreased interferon-γ (IFN-γ)-producing CD4(+) Th1 cell numbers in the colon. Wnt5a was highly expressed in stromal fibroblasts in ulcerative lesions in the DSS-treated mice and inflammatory bowel disease patients. Dendritic cells (DCs) isolated from the colon of Wnt5a and Ror2 deficient mice reduced the ability to differentiate naïve CD4(+) T cells to IFN-γ-producing CD4(+) Th1 cells. In vitro experiments demonstrated that the Wnt5a-Ror2 signaling axis augmented the DCs priming effect of IFN-γ, leading to enhanced lipopolysaccharide (LPS)-induced interleukin (IL)-12 expression. Taken together, these results suggest that Wnt5a promotes IFN-γ signaling, leading to IL-12 expression in DCs, and thereby inducing Th1 differentiation in colitis.
Souji Ibuka, Shinji Matsumoto, Shinsuke Fujii and Akira Kikuchi : The P2Y2 receptor promotes Wnt3a- and EGF-induced epithelial tubular formation by IEC6 cells by binding to integrins., Journal of Cell Science, Vol.128, No.11, 2156-2168, 2015.
(Summary)
Epithelial tubular structures are essential units in various organs. Here, we used rat intestinal epithelial IEC6 cells to investigate tubulogenesis and we found that tubular formation was induced by a combination of Wnt3a and EGF signaling during three-dimensional culture. Wnt3a and EGF induced the expression of the P2Y2 receptor (P2Y2R, also known as P2RY2), and knockdown of P2Y2R suppressed tubular formation. A P2Y2R mutant that lacks nucleotide responsiveness rescued the phenotypes resulting from P2Y2R knockdown, suggesting that nucleotide-dependent responses are not required for P2Y2R functions in tubular formation. The Arg-Gly-Asp (RGD) sequence of P2Y2R has been shown to interact with integrins, and a P2Y2R mutant lacking integrin-binding activity was unable to induce tubular formation. P2Y2R expression inhibited the interaction between integrins and fibronectin, and induced cell morphological changes and proliferation. Inhibition of integrin and fibronectin binding by treatment with the cyclic RGD peptide and fibronectin knockdown induced tubular formation in the presence of EGF alone, but a fibronectin coat suppressed Wnt3a- and EGF-induced tubular formation. These results suggest that Wnt3a- and EGF-induced P2Y2R expression causes tubular formation by preventing the binding of integrins and fibronectin rather than by mediating nucleotide responses.
Hideki Yamamoto, Chihiro Awada, Shinji Matsumoto, Tomoyuki Kaneiwa, Takayuki Sugimoto, Toshifumi Takao and Akira Kikuchi : Basolateral secretion of Wnt5a in polarized epithelial cells is required for apical lumen formation., Journal of Cell Science, Vol.128, No.5, 1051-1063, 2015.
(Summary)
Wnt5a regulates planar cell polarity in epithelial cells, but it remains to be determined whether Wnt5a and its receptors are sorted apically or basolaterally, and how Wnt5a signaling is involved in apical and basolateral polarization. We found that Wnt5a was secreted basolaterally in polarized kidney epithelial cells. The basolateral secretion of Wnt5a required Wntless (Wls), clathrin and adaptor protein 1 (AP-1). Wnt5a receptors were also localized to the basolateral membranes, but their sorting did not require Wls. Wnt5a-induced signaling was stimulated more efficiently at the basolateral side than the apical side of epithelial cells. Knockdown of Wnt5a delayed apical lumen formation of the epithelial cyst, and these phenotypes were rescued by wild-type Wnt5a, but not by a Wnt5a mutant that is secreted apically. Although apoptosis was not required for apical lumen formation in a wild-type cyst, apoptosis was necessary for eliminating luminal cells in a Wnt5a-depleted cyst. These results suggest that Wnt5a and its receptors are sorted to their correct destination by different mechanisms and that the basolateral secretion of Wnt5a is necessary for apical lumen formation in the epithelial cyst.
Shinsuke Fujii, Shinji Matsumoto, Satoshi Nojima, Eiichi Morii and Akira Kikuchi : Arl4c expression in colorectal and lung cancers promotes tumorigenesis and may represent a novel therapeutic target., Oncogene, Vol.34, No.37, 4834-4844, 2014.
(Summary)
We recently demonstrated that expression of ADP-ribosylation factor (ARF)-like 4c (Arl4c) induced by a combination of Wnt/β-catenin and epidermal growth factor/Ras signaling in normal epithelial cells grown in three-dimensional culture promotes cellular migration and proliferation, resulting in formation of tube-like structures, suggesting the involvement of Arl4c in epithelial morphogenesis. It is conceivable that there could be a common mechanism between epithelial morphogenesis and carcinogenesis. Therefore the current study was conducted to investigate whether Arl4c might be involved in tumorigenesis. Immunohistochemical analyses of tissue specimens obtained from colorectal and lung cancer patients revealed that Arl4c was not observed in non-tumor regions but was strongly expressed at high frequencies in tumor lesions. Inhibition of Wnt/β-catenin or Ras/mitogen-activated protein kinase signaling reduced Arl4c mRNA levels in HCT116 colorectal cancer cells and A549 lung cancer cells. Knockdown of Arl4c inhibited Rac activity and also prevented nuclear localization of yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) in these cancer cells. Arl4c-depleted cancer cells consistently showed decreased migration, invasion and proliferation capabilities both in vitro and in vivo. Furthermore, direct injection of Arl4c small interfering RNA (siRNA) into HCT116 cell-derived tumors (in vivo treatment with siRNA) inhibited tumor growth in immunodeficient mice. These results suggest that Arl4c is involved in tumorigenesis and might represent a novel therapeutic target for suppressing proliferation and invasion of colorectal and lung cancer cells.
Shinji Matsumoto, Shinsuke Fujii, Akira Sato, Souji Ibuka, Yoshinori Kagawa, Masaru Ishii and Akira Kikuchi : A combination of Wnt and growth factor signaling induces Arl4c expression to form epithelial tubular structures., The EMBO Journal, Vol.33, No.7, 702-718, 2014.
(Summary)
Growth factor-dependent epithelial morphological changes and proliferation are essential for the formation of tubular structures, but the underlying molecular mechanisms are poorly understood. Co-stimulation with Wnt3a and epidermal growth factor (Wnt3a/EGF) induced development of tubes consisting of intestinal epithelial cells by inducing expression of Arl4c, an Arf-like small GTP-binding protein, in three-dimensional culture, while stimulation with Wnt3a or EGF alone did not. Arl4c expression resulted in rearrangement of the cytoskeleton through activation of Rac and inactivation of Rho properly, which promoted cell growth by inducing nuclear translocation of Yes-associated protein and transcriptional co-activator with PDZ-binding motif (YAP/TAZ) in leading cells. Arl4c was expressed in ureteric bud tips and pretubular structures in the embryonic kidney. In an organoid culture assay, Wnt and fibroblast growth factor signaling simultaneously induced elongation and budding of kidney ureteric buds through Arl4c expression. YAP/TAZ was observed in the nucleus of extending ureteric bud tips. Thus, Arl4c expression induced by a combination of growth factor signaling mechanisms is involved in tube formation.
The mechanism behind the spatiotemporal control of cancer cell dynamics and its possible association with cell proliferation has not been well established. By exploiting the intravital imaging technique, we found that cancer cell motility and invasive properties were closely associated with the cell cycle. In vivo inoculation of human colon cancer cells bearing fluorescence ubiquitination-based cell cycle indicator (Fucci) demonstrated an unexpected phenomenon: S/G2/M cells were more motile and invasive than G1 cells. Microarray analyses showed that Arhgap11a, an uncharacterized Rho GTPase-activating protein (RhoGAP), was expressed in a cell-cycle-dependent fashion. Expression of ARHGAP11A in cancer cells suppressed RhoA-dependent mechanisms, such as stress fiber formation and focal adhesion, which made the cells more prone to migrate. We also demonstrated that RhoA suppression by ARHGAP11A induced augmentation of relative Rac1 activity, leading to an increase in the invasive properties. RNAi-based inhibition of Arhgap11a reduced the invasion and in vivo expansion of cancers. Additionally, analysis of human specimens showed the significant up-regulation of Arhgap11a in colon cancers, which was correlated with clinical invasion status. The present study suggests that ARHGAP11A, a cell cycle-dependent RhoGAP, is a critical regulator of cancer cell mobility and is thus a promising therapeutic target in invasive cancers.
Hidetoshi Gon, Katsumi Fumoto, Yonson Ku, Shinji Matsumoto and Akira Kikuchi : Wnt5a signaling promotes apical and basolateral polarization of single epithelial cells., Molecular Biology of the Cell, Vol.24, No.23, 3764-3774, 2013.
(Summary)
Single epithelial-derived tumor cells have been shown to induce apical and basolateral (AB) polarity by expression of polarization-related proteins. However, physiological cues and molecular mechanisms for AB polarization of single normal epithelial cells are unclear. When intestinal epithelial cells 6 (IEC6 cells) were seeded on basement membrane proteins (Matrigel), single cells formed an F-actin cap on the upper cell surface, where apical markers accumulated, and a basolateral marker was localized to the rest of the cell surface region, in a Wnt5a signaling-dependent manner. However, these phenotypes were not induced by type I collagen. Rac1 activity in the noncap region was higher than that in the cap region, whereas Rho activity increased toward the cap region. Wnt5a signaling activated and inhibited Rac1 and RhoA, respectively, independently through Tiam1 and p190RhoGAP-A, which formed a tertiary complex with Dishevelled. Furthermore, Wnt5a signaling through Rac1 and RhoA was required for cystogenesis of IEC6 cells. These results suggest that Wnt5a promotes the AB polarization of IEC6 cells through regulation of Rac and Rho activities in a manner dependent on adhesion to specific extracellular matrix proteins.
(Keyword)
Adaptor Proteins, Signal Transducing / Animals / Cell Polarity / Cell Shape / Chlorocebus aethiops / Collagen / Dishevelled Proteins / Drug Combinations / Enterocytes / Epithelial Cells / Green Fluorescent Proteins / Guanine Nucleotide Exchange Factors / HEK293 Cells / HeLa Cells / Humans / Laminin / Microvilli / Neoplasm Proteins / Phosphoproteins / Protein Transport / Proteoglycans / Rats / Repressor Proteins / Signal Transduction / T-Lymphoma Invasion and Metastasis-inducing Protein 1 / Vero Cells / Wnt Proteins / Wnt-5a Protein / rac1 GTP-Binding Protein / rho GTP-Binding Proteins
Maki Ishida-Takagishi, Atsushi Enomoto, Naoya Asai, Kaori Ushida, Takashi Watanabe, Takahiko Hashimoto, Takuya Kato, Liang Weng, Shinji Matsumoto, Masato Asai, Yoshiki Murakumo, Kozo Kaibuchi, Akira Kikuchi and Masahide Takahashi : The Dishevelled-associating protein Daple controls the non-canonical Wnt/Rac pathway and cell motility., Nature Communications, Vol.3, 859, 2012.
(Summary)
Dishevelled is the common mediator of canonical and non-canonical Wnt signalling pathways, which are important for embryonic development, tissue maintenance and cancer progression. In the non-canonical Wnt signalling pathway, the Rho family of small GTPases acting downstream of Dishevelled has essential roles in cell migration. The mechanisms by which the non-canonical Wnt signalling pathway regulates Rac activation remain unknown. Here we show that Daple (Dishevelled-associating protein with a high frequency of leucine residues) regulates Wnt5a-mediated activation of Rac and formation of lamellipodia through interaction with Dishevelled. Daple increases the association of Dishevelled with an isoform of atypical protein kinase C, consequently promoting Rac activation. Accordingly, Daple deficiency impairs migration of fibroblasts and epithelial cells during wound healing in vivo. These findings indicate that Daple interacts with Dishevelled to direct the Dishevelled/protein kinase λ protein complex to activate Rac, which in turn mediates the non-canonical Wnt signalling pathway required for cell migration.
(Keyword)
Adaptor Proteins, Signal Transducing / Animals / Blotting, Western / Carrier Proteins / Cell Line / Cell Movement / Cells, Cultured / Dishevelled Proteins / Fibroblasts / Humans / Immunohistochemistry / Immunoprecipitation / Keratinocytes / Mice / Mice, Knockout / Models, Biological / Phosphoproteins / Protein Binding / Protein Kinase C / Signal Transduction / Wnt Proteins / Wnt-5a Protein
Hiroshi Sakane, Hideki Yamamoto, Shinji Matsumoto, Akira Sato and Akira Kikuchi : Localization of glypican-4 in different membrane microdomains is involved in the regulation of Wnt signaling., Journal of Cell Science, Vol.125, No.Pt 2, 449-460, 2012.
(Summary)
Glypicans are members of the heparan sulfate proteoglycans (HSPGs) and are involved in various growth factor signaling mechanisms. Although HSPGs affect the β-catenin-dependent and -independent pathways of Wnt signaling, how they regulate distinct Wnt pathways is not clear. It has been suggested that the β-catenin-dependent pathway is initiated through receptor endocytosis in lipid raft microdomains and the independent pathway is activated through receptor endocytosis in non-lipid raft microdomains. Here, evidence is presented that glypican-4 (GPC4) is localized to both membrane microdomains and that the localization affects its ability to regulate distinct Wnt pathways. GPC4 bound to Wnt3a and Wnt5a, which activate the β-catenin-dependent and -independent pathways, respectively, and colocalized with Wnts on the cell surface. LRP6, one of Wnt3a coreceptors, was present in lipid raft microdomains, whereas Ror2, one of Wnt5a coreceptors, was localized to non-lipid raft microdomains. Expression of GPC4 enhanced the Wnt3a-dependent β-catenin pathway and the Wnt5a-dependent β-catenin-independent pathway, and knockdown of GPC4 suppressed both pathways. A GPC4 mutant that was localized to only non-lipid raft microdomains inhibited the β-catenin-dependent pathway but enhanced the β-catenin-independent pathway. These results suggest that GPC4 concentrates Wnt3a and Wnt5a to the vicinity of their specific receptors in different membrane microdomains, thereby regulating distinct Wnt signaling.
Shinji Matsumoto and Akira Kikuchi : Regulation of focal adhesion dynamics by Wnt5a signaling., Methods in Molecular Biology, Vol.839, 215-227, 2012.
(Summary)
Wnt5a is a representative ligand that activates the β-catenin-independent pathway of Wnt signaling in mammals. This pathway might be related to planar cell polarity signaling in Drosophila. Because reliable biochemical assays to measure Wnt5a pathway activity have not yet been established, we examined whether Wnt5a signaling stimulates focal adhesion turnover in migrating cells using live immunofluorescence imaging and immunocytochemical analysis. These assays demonstrated that the Wnt5a pathway cooperates with integrin signaling to regulate cell migration and adhesion through focal adhesion dynamics.
(Keyword)
Animals / Cell Movement / Cell Survival / Chlorocebus aethiops / Focal Adhesions / Frizzled Receptors / Gene Knockdown Techniques / HeLa Cells / Humans / Immunohistochemistry / Integrin beta1 / Intracellular Space / Molecular Imaging / Plasmids / Protein Transport / Proto-Oncogene Proteins / RNA, Small Interfering / Signal Transduction / Transfection / Vero Cells / Wnt Proteins / Wnt-5a Protein
Hideaki Hanaki, Hideki Yamamoto, Hiroshi Sakane, Shinji Matsumoto, Hideki Ohdan, Akira Sato and Akira Kikuchi : An anti-Wnt5a antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis., Molecular Cancer Therapeutics, Vol.11, No.2, 298-307, 2011.
(Summary)
Wnt5a is a representative ligand that activates the β-catenin-independent pathway in Wnt signaling. It was reported that the expression of Wnt5a in human gastric cancer is associated with aggressiveness and poor prognosis and that knockdown of Wnt5a reduces the ability of gastric cancer cells to metastasize in nude mice. Therefore, Wnt5a and its signaling pathway might be important targets for the therapy of gastric cancer. The aim of this study was to examine whether an anti-Wnt5a antibody affects metastasis of gastric cancer cells. One anti-Wnt5a polyclonal antibody (pAb5a-5) inhibited migration and invasion activities in vitro of gastric cancer cells with a high expression level of Wnt5a. Previously, it was shown that Wnt5a induces the internalization of receptors, which is required for Wnt5a-dependent activation of Rac1. pAb5a-5 inhibited Wnt5a-dependent internalization of receptors, thereby suppressed Wnt5a-dependent activation of Rac1. Laminin γ2 is one of target genes of Wnt5a signaling and Rac1 was involved in its expression. pAb5a-5 also inhibited Wnt5a-dependent expression of laminin γ2. In an experimental liver metastasis assay, gastric cancer cells were introduced into the spleens of nude mice. Laminin γ2 was required for liver metastatic ability of gastric cancer cells in vivo. Furthermore, intraperitoneal injection of pAb5a-5 inhibited the metastatic ability of gastric cancer cells. These results suggest that an anti-Wnt5a antibody was capable of suppressing Wnt5a-dependent internalization of receptors, resulting in the prevention of metastasis of gastric cancer cells by inhibiting the activation of Rac1 and the expression of laminin γ2.
Shinji Matsumoto, Katsumi Fumoto, Tetsuji Okamoto, Kozo Kaibuchi and Akira Kikuchi : Binding of APC and dishevelled mediates Wnt5a-regulated focal adhesion dynamics in migrating cells., The EMBO Journal, Vol.29, No.7, 1192-1204, 2010.
(Summary)
Wnt5a is a representative ligand that activates the Wnt/beta-catenin-independent pathway, resulting in the regulation of cell adhesion, migration, and polarity, but its molecular mechanism is poorly understood. This report shows that Dishevelled (Dvl) binds to adenomatous polyposis coli (APC) gene product, and this binding is enhanced by Wnt5a. Dvl was involved in the stabilization of the plus end dynamics of microtubules as well as APC. Frizzled2 (Fz2) was present with Wnt5a at the leading edge of migrating cells and formed a complex with APC through Dvl. Fz2 also interacted with integrins at the leading edge, and Dvl and APC associated with and activated focal adhesion kinase and paxillin. The binding of APC to Dvl enhanced the localization of paxillin to the leading edge and was involved in Wnt5a-dependent focal adhesion turnover. Furthermore, this new Wnt5a signalling pathway was important for the epithelial morphogenesis in the three-dimensional culture. These results suggest that the functional and physical interaction of Dvl and APC is involved in Wnt5a/Fz2-dependent focal adhesion dynamics during cell migration and epithelial morphogenesis.
(Keyword)
Adaptor Proteins, Signal Transducing / Animals / COS Cells / Cell Adhesion / Cell Line / Cell Movement / Chlorocebus aethiops / Dishevelled Proteins / Epithelial Cells / Focal Adhesions / Frizzled Receptors / Genes, APC / HeLa Cells / Humans / Phosphoproteins / Protein Binding / Vero Cells / Wnt Proteins
Yasuto FUKUI, Shigeaki TORATANI, Koichi KOIZUMI, Shinji Matsumoto, Yasutaka HAYASHIDO and Tetsuji OKAMOTO : A case of intramuscular lipoma extending to the infratemporal fossa that was associated with mental nerve neuropathy as an initial symptom, Jpn. J. Oral Maxillofac. Surg., Vol.55, No.11, 580-584, 2009.
Shinji Matsumoto and Akira Kikuchi : Wnt/β-catenin signaling pathway in liver biology and tumorigenesis., In Vitro Cellular & Developmental Biology. Animal, Vol.60, No.5, 466-481, Feb. 2024.
(Summary)
The Wnt/β-catenin pathway is an evolutionarily conserved signaling pathway that controls fundamental physiological and pathological processes by regulating cell proliferation and differentiation. The Wnt/β-catenin pathway enables liver homeostasis by inducing differentiation and contributes to liver-specific features such as metabolic zonation and regeneration. In contrast, abnormalities in the Wnt/β-catenin pathway promote the development and progression of hepatocellular carcinoma (HCC). Similarly, hepatoblastoma, the most common childhood liver cancer, is frequently associated with β-catenin mutations, which activate Wnt/β-catenin signaling. HCCs with activation of the Wnt/β-catenin pathway have unique gene expression patterns and pathological and clinical features. Accordingly, they are highly differentiated with retaining hepatocyte-like characteristics and tumorigenic. Activation of the Wnt/β-catenin pathway in HCC also alters the state of immune cells, causing "immune evasion" with inducing resistance to immune checkpoint inhibitors, which have recently become widely used to treat HCC. Activated Wnt/β-catenin signaling exhibits these phenomena in liver tumorigenesis through the expression of downstream target genes, and the molecular basis is still poorly understood. In this review, we describe the physiological roles of Wnt/b-catenin signaling and then discuss their characteristic changes by the abnormal activation of Wnt/b-catenin signaling. Clarification of the mechanism would contribute to the development of therapeutic agents in the future.
Akira Kikuchi, Shinji Matsumoto and Ryota Sada : Dickkopf signaling, beyond Wnt-mediated biology., Seminars in Cell & Developmental Biology, Vol.125, 55-65, Nov. 2021.
(Summary)
Dickkopf1 (DKK1) was originally identified as a secreted protein that antagonizes Wnt signaling. Although DKK1 is essential for the developmental process, its functions in postnatal and adult life are unclear. However, evidence is accumulating that DKK1 is involved in tumorigenesis in a manner unrelated to Wnt signaling. In addition, recent studies have revealed that DKK1 may control immune reactions, although the relationship of this to Wnt signaling is unknown. Other DKK family members, DKK2-4, are likely to have their own functions. Here, we review the possible novel functions of DKKs. We summarize the characteristics of receptors of DKKs and the signaling mechanisms through DKKs and their receptors, provide evidence showing that DKKs are involved in tumor aggressiveness independently of Wnt signaling, and emphasize promising cancer therapies targeting DKKs and receptors. Lastly, we discuss various physiological and pathological processes controlled by DKKs.
Shinji Matsumoto and Akira Kikuchi : Wnt signaling pathways in cancers: key targets and implications in cancer therapy, Leading Author's, Vol.7, e009, 2018.
Shinji Matsumoto, Shinsuke Fujii and Akira Kikuchi : Arl4c is a key regulator of tubulogenesis and tumourigenesis as a target gene of Wnt-β-catenin and growth factor-Ras signalling., The Journal of Biochemistry, Vol.161, No.1, 27-35, Nov. 2016.
(Summary)
Epithelial tubular morphogenesis (tubulogenesis) is a fundamental morphogenetic process of many epithelial organs. In this developmental process, epithelial cells migrate, proliferate, polarize and differentiate towards surrounding mesenchymal tissue to form tubule structures. Although epithelial tissue structures are basically stable in the postnatal period, epithelial cells regain highly proliferative and invasive potentials within mesenchymal tissue during tumour formation (tumourigenesis). Therefore, there must be a common molecular basis orchestrating the cellular behaviours involved in both tubulogenesis and tumourigenesis. ADP-ribosylation factor (Arf)-like protein 4c (Arl4c), which belongs to the small GTP-binding protein family, is expressed by the simultaneous activation of Wnt-β-catenin and growth factor-Ras-mitogen-activated protein kinase signalling, was identified as an essential regulator of tubulogenesis. Arl4c expression was also involved in the tumour formation of colorectal and lung cancers. In this review, we focus on Arl4c as a novel Wnt signal target molecule that links epithelial tubulogenesis to tumourigenesis.
Shinji Matsumoto and 菊池 章 : Role of Wnt 5a signaling in the regulation of cell polarity, migration, and adhesion, 生体の科学, Vol.64, No.3, 226-231, Jun. 2013.
Akira Kikuchi, Hideki Yamamoto, Akira Sato and Shinji Matsumoto : New insights into the mechanism of Wnt signaling pathway activation., International Review of Cell and Molecular Biology, Vol.291, 21-71, 2011.
(Summary)
Wnts compromise a large family of secreted, hydrophobic glycoproteins that control a variety of developmental and adult processes in all metazoan organisms. Recent advances in the Wnt-signal studies have revealed that distinct Wnts activate multiple intracellular cascades that regulate cellular proliferation, differentiation, migration, and polarity. Although the mechanism by which Wnts regulate different pathways selectively remains to be clarified, evidence has accumulated that in addition to the formation of ligand-receptor pairs, phosphorylation of receptors, receptor-mediated endocytosis, acidification, and the presence of cofactors, such as heparan sulfate proteoglycans, are also involved in the activation of specific Wnt pathways. Here, we review the mechanism of activation in Wnt signaling initiated on the cell-surface membrane. In addition, the mechanisms for fine-tuning by cross talk between Wnt and other signaling are also discussed.
Kikuchi Akira, Shinji Matsumoto and Harada Akikazu : Oncogenic transcription difference between Wnt signal-activated hepatocellular carcinoma and colorectal carcinoma., Gordon Conference, Jul. 2023.
2.
Shinji Matsumoto, Harada Akikazu and Kikuchi Akira : GREB1 drives HNF4α-dependent oncogenic transcription and tumor growth in Wnt signal-activated hepatocellular carcinoma., EMBO Workshop Wnt Meeting 2022., Nov. 2022.
3.
Kikuchi Akira and Shinji Matsumoto : Regulation of cell adhesion and migration by Wnt5a signaling., Euro Wnt meeting 2009., Aug. 2009.
4.
Shinji Matsumoto : Dishevelled/APC complex regulates cell adhesion and migration through mobilizing FAK and Paxillin., The Japan-Korea Joint Symposium on Wnt Signaling and Human Diseases., Nov. 2008.