Attenuation of EGF receptor signaling by a metastasis suppressor, the tetraspanin CD82/KAI-1

Abstract

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.

Tetraspanin KAI1/CD82 suppresses invasion by inhibiting integrin-dependent crosstalk with c-Met receptor and Src kinases

“…c-Met, the receptor for HGF/SF, is known to regulate migration and invasion and has been implicated in promoting metastasis in many different kinds of cancers (Pisters et al, 1995;Birchmeier et al, 1997Birchmeier et al, , 2003Wang et al, 2001), including prostate cancer (Humphrey et al, 1995;Nishimura et al, 1998;Knudsen et al, 2002;van Leenders et al, 2002;Nakashiro et al, 2003;Knudsen and Edlund, 2004). Previous studies in a mammary tumor cell line demonstrated that CD82 expression attenuated EGF-mediated EGFR signaling and reduced migration (Odintsova et al, 2000). In PC3 or DU145 cells, we did not observe significant changes in integrin-induced activation of EGFR or EGFR levels due to CD82 expression (not shown).…”

“…EGF-mediated signaling and wound closure were shown to be attenuated after ectopic expression of CD82 in a breast tumor cell line (Odintsova et al, 2000). Accelerated endocytosis of the EGFR-EGF complex was suggested to be the cause for signal attenuation.…”

“…Tetraspanins lack intrinsic activity and their effects are mediated by protein interactions. Several different proteins have been shown to associate with CD82 (Yunta and Lazo, 2003), including a3b1, a4b1, a5b1, and a6b1 integrins (Berditchevski and Odintsova, 1999;Berditchevski, 2001;Yunta and Lazo, 2003); the serine/threonine kinase PKCa (Berditchevski and Odintsova, 1999;Berditchevski, 2001;Zhang et al, 2001); B-cell receptors CD4, CD8, and CD19 (Imai et al, 1995;Mannion et al, 1996;Hammond et al, 1998); other tetraspanins including CD81, CD63, and CD9 (Vogt et al, 2002); receptor tyrosine kinases EGFR and ErbB2 (Odintsova et al, 2000(Odintsova et al, , 2003; an Ig super family molecule EW12 (Zhang et al, 2003b); and a newly identified tetraspanin molecule, kitenin, which is expressed in gastric cancers (Lee et al, 2004b).…”

“…Furthermore, integrins have been shown to activate several receptor tyrosine kinases in a ligandindependent manner, including EGFR, c-Met, PDGFR, and Ron (Sundberg and Rubin, 1996;Wang et al, 1996Wang et al, , 2001Moro et al, 1998Moro et al, , 2002Danilkovitch-Miagkova et al, 2000;Bill et al, 2004). Both integrins and receptor tyrosine kinases can interact with CD82 (Hemler, 1998;Odintsova et al, 2000). Therefore, one mechanism by which CD82 may control tumor metastasis is by regulating the function of integrins and their ability to cooperate with receptor tyrosine kinases.…”

CXCR4/CXCL12 expression and signalling in kidney cancer

“…A most interesting molecule in this group was CD82 (also termed kangai 1, suppressor of tumourigenicity 6, KAI1), as it was the only molecule being upregulated after 6 h (factor, 2.3) and 18 h (factor, 2.2) of CXCL12a stimulation, respectively. The transmembrane protein CD82 is directly associated with the epidermal growth factor receptor (EGFR) and other tyrosine kinase receptors and accelerates desensitisation of tyrosine receptor induced signalling correlated with an increased rate of receptor endocytosis (Odintsova et al, 2000). This attenuation of EGFR signalling by CD82 explains for its recently identified role as metastasis suppressor gene for prostate and pancreatic cancer (Dong et al, 1995;Guo et al, 1996).…”