CADM1 interacts with Tiam1 and promotes invasive phenotype of human T-cell leukemia virus type I-transformed cells and adult T-cell leukemia cells.
CADM1 encodes a multifunctional immunoglobulin-like cell adhesion molecule whose cytoplasmic domain contains a type II PSD95/Dlg/ZO-1 (PDZ)-binding motif (BM) for associating with other intracellular proteins. Although CADM1 lacks expression in T lymphocytes of healthy individuals, it is overexpressed in adult T-cell leukemia-lymphoma (ATL) cells. It has been suggested that the expression of CADM1 protein promotes infiltration of leukemic cells into various organs and tissues, which is one of the frequent clinical manifestations of ATL. Amino acid sequence alignment revealed that Tiam1 (T-lymphoma invasion and metastasis 1), a Rac-specific guanine nucleotide exchange factor, has a type II PDZ domain similar to those of membrane-associated guanylate kinase homologs (MAGUKs) that are known to bind to the PDZ-BM of CADM1. In this study, we demonstrated that the cytoplasmic domain of CADM1 directly interacted with the PDZ domain of Tiam1 and induced formation of lamellipodia through Rac activation in HTLV-I-transformed cell lines as well as ATL cell lines. Our results indicate that Tiam1 integrates signals from CADM1 to regulate the actin cytoskeleton through Rac activation, which may lead to tissue infiltration of leukemic cells in ATL patients.
Masuda
Mari
M
Genetics Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan. Electronic address: mamasuda@ncc.go.jp.
Maruyama
Tomoko
T
Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Ohta
Tsutomu
T
Genetics Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Ito
Akihiko
A
Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
Hayashi
Tomayoshi
T
Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
Tsukasaki
Kunihiko
K
Department of Molecular Medicine and Hematology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
Kamihira
Shimeru
S
Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523, Japan.
Yamaoka
Shoji
S
Department of Molecular Virology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Hoshino
Hiroo
H
Department of Virology and Preventive Medicine, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan.
Yoshida
Teruhiko
T
Genetics Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Watanabe
Toshiki
T
Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, University of Tokyo, Tokyo 108-8639, Japan.
Stanbridge
Eric J
EJ
Department of Microbiology and Molecular Genetics, College of Medicine, University of California, Irvine, California 92697.
Murakami
Yoshinori
Y
Tumor Suppression and Functional Genomics Project, National Cancer Center Research Institute, Tokyo 104-0045, Japan; Division of Molecular Pathology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan. Electronic address: ymurakam@ims.u-tokyo.ac.jp.
D000595:Amino Acid Sequence; D001483:Base Sequence; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D045744:Cell Line, Tumor; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D015368:Human T-lymphotropic virus 1 / Q000472:pathogenicity*; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry / Q000378:metabolism*; D007150:Immunohistochemistry; D015458:Leukemia, T-Cell / Q000473:pathology*; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism*; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering; D017386:Sequence Homology, Amino Acid; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000378:metabolism*
C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D020662:Guanine Nucleotide Exchange Factors; D007136:Immunoglobulins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; D025521:Tumor Suppressor Proteins