The palmitoylation of metastasis suppressor KAI1/CD82 is important for its motility- and invasiveness-inhibitory activity.
The cancer metastasis suppressor protein KAI1/CD82 is a member of the tetraspanin superfamily. Recent studies have demonstrated that tetraspanins are palmitoylated and that palmitoylation contributes to the organization of tetraspanin webs or tetraspanin-enriched microdomains. However, the effect of palmitoylation on tetraspanin-mediated cellular functions remains obscure. In this study, we found that tetraspanin KAI1/CD82 was palmitoylated when expressed in PC3 metastatic prostate cancer cells and that palmitoylation involved all of the cytoplasmic cysteine residues proximal to the plasma membrane. Notably, the palmitoylation-deficient KAI1/CD82 mutant largely reversed the wild-type KAI1/CD82's inhibitory effects on migration and invasion of PC3 cells. Also, palmitoylation regulates the subcellular distribution of KAI1/CD82 and its association with other tetraspanins, suggesting that the localized interaction of KAI1/CD82 with tetraspanin webs or tetraspanin-enriched microdomains is important for KAI1/CD82's motility-inhibitory activity. Moreover, we found that KAI1/CD82 palmitoylation affected motility-related subcellular events such as lamellipodia formation and actin cytoskeleton organization and that the alteration of these processes likely contributes to KAI1/CD82's inhibition of motility. Finally, the reversal of cell motility seen in the palmitoylation-deficient KAI1/CD82 mutant correlates with regaining of p130(CAS)-CrkII coupling, a signaling step important for KAI1/CD82's activity. Taken together, our results indicate that palmitoylation is crucial for the functional integrity of tetraspanin KAI1/CD82 during the suppression of cancer cell migration and invasion.
Zhou
Bin
B
Vascular Biology Center and Department of Medicine and Department of Molecular Science, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
Liu
Li
L
Reddivari
Muralidhar
M
Zhang
Xin A
XA
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D050719:Crk-Associated Substrate Protein; D006801:Humans; D051861:Kangai-1 Protein; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D010168:Palmitates / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk; D051381:Rats; D050717:Retinoblastoma-Like Protein p130; D013347:Subcellular Fractions / Q000378:metabolism; D014162:Transfection
D015703:Antigens, CD; C493841:BCAR1 protein, human; C493842:Bcar1 protein, mouse; C493843:Bcar1 protein, rat; C497688:CD82 protein, human; C497689:Cd82 antigen, mouse; C497690:Cd82 protein, rat; C493872:Crk protein, rat; D050719:Crk-Associated Substrate Protein; D051861:Kangai-1 Protein; D008562:Membrane Glycoproteins; D010168:Palmitates; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D050717:Retinoblastoma-Like Protein p130