Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression.
CD82, also known as KAI1, was recently identified as a prostate cancer metastasis suppressor gene on human chromosome 11p1.2 (ref. 1). The product of CD82 is KAI1, a 40- to 75-kDa tetraspanin cell-surface protein also known as the leukocyte cell-surface marker CD82 (refs. 1,2). Downregulation of KAI1 has been found to be clinically associated with metastatic progression in a variety of cancers, whereas overexpression of CD82 specifically suppresses tumor metastasis in various animal models. To define the mechanism of action of KAI1, we used a yeast two-hybrid screen and identified an endothelial cell-surface protein, DARC (also known as gp-Fy), as an interacting partner of KAI1. Our results indicate that the cancer cells expressing KAI1 attach to vascular endothelial cells through direct interaction between KAI1 and DARC, and that this interaction leads to inhibition of tumor cell proliferation and induction of senescence by modulating the expression of TBX2 and p21. Furthermore, the metastasis-suppression activity of KAI1 was significantly compromised in DARC knockout mice, whereas KAI1 completely abrogated pulmonary metastasis in wild-type and heterozygous littermates. These results provide direct evidence that DARC is essential for the function of CD82 as a suppressor of metastasis.
Bandyopadhyay
Sucharita
S
Southern Illinois University School of Medicine, Department of Medical Microbiology, Immunology and Cell Biology, 801 N. Rutledge Street, PO Box 19626, Springfield, Illinois 62794-9626, USA.
Zhan
Rui
R
Chaudhuri
Asok
A
Watabe
Misako
M
Pai
Sudha K
SK
Hirota
Shigeru
S
Hosobe
Sadahiro
S
Tsukada
Taisei
T
Miura
Kunio
K
Takano
Yukio
Y
Saito
Ken
K
Pauza
Mary E
ME
Hayashi
Sunao
S
Wang
Ying
Y
Mohinta
Sonia
S
Mashimo
Tomoyuki
T
Iiizumi
Megumi
M
Furuta
Eiji
E
Watabe
Kounosuke
K
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004375:Duffy Blood-Group System / Q000737:chemistry / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006801:Humans; D051861:Kangai-1 Protein / Q000737:chemistry / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism
C473745:ACKR1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004375:Duffy Blood-Group System; D051861:Kangai-1 Protein; D008562:Membrane Glycoproteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins