Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1.
The 'metastasis suppressor' CD82/KAI-1, a member of the tetraspanin superfamily of transmembrane proteins, is widely distributed in normal tissues [1], and has been shown to be suppressed in the advanced stages of various epithelial malignancies [2-6]. Although the physiological relevance of this change is unknown, in vitro data show that ectopically expressed CD82/KAI-1 can suppress tumor cell migration, a process underlying the dissemination of tumor cells in vivo [5]. The function of CD82/KAI-1 is not known and it has been proposed that association of CD82/KAI-1 with other cell-surface proteins may be pivotal in directing its biological activities [7,8]. We show here that the CD82/KAI-1 tetraspanin is directly associated with the EGF receptor (EGFR), and that ectopic expression of CD82/KAI-1 in epithelial cells specifically suppresses EGF-induced lamellipodial extensions and cell migration. In cells expressing CD82/KAI-1, the initial activation of EGFR is not affected, but subsequent desensitization of EGF-induced signaling occurs more rapidly. This attenuation is correlated with an increased rate of receptor endocytosis. These results identify CD82/KAI-1 as a new regulator of EGF-induced signaling and show that the association of EGFR with the tetraspanin is critical in EGFR desensitization.
Odintsova
E
E
CRC Institute for Cancer Studies, The University of Birmingham, Edgbaston, UK.
Sugiura
T
T
Berditchevski
F
F
D015703:Antigens, CD / Q000378:metabolism*; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051861:Kangai-1 Protein; D008562:Membrane Glycoproteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; C497688:CD82 protein, human; D051861:Kangai-1 Protein; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors