Requirement of the p130CAS-Crk coupling for metastasis suppressor KAI1/CD82-mediated inhibition of cell migration.
KAI1/CD82 protein is a member of the tetraspanin superfamily and has been rediscovered as a cancer metastasis suppressor. The mechanism of KAI1/CD82-mediated suppression of cancer metastasis remains to be established. In this study, we found that migration of the metastatic prostate cancer cell line Du145 was substantially inhibited when KAI1/CD82 was expressed. The expression of focal adhesion kinase (FAK) and Lyn, a Src family tyrosine kinase and substrate of FAK, was up-regulated at both RNA and protein levels upon KAI1/CD82 expression. The activation of FAK and Lyn, however, remained unchanged in Du145-KAI1/CD82 cells. As a downstream target of FAK-Lyn signaling, the p130CAS (Crk-associated substrate) protein was decreased upon the expression of KAI1/CD82. Consequently, less p130CAS-CrkII complex, which functions as a "molecular switch" in cell motility, was formed in Du145-KAI1/CD82 cells. To confirm that the p130CAS-CrkII complex is indeed important for the motility inhibition by KAI1/CD82, overexpression of p130CAS in Du145-KAI1/CD82 cells increased the formation of p130CAS-CrkII complex and largely reversed the KAI1/CD82-mediated inhibition of cell motility. Taken together, our studies indicate the following: 1) signaling of FAK-Lyn-p130CAS-CrkII pathway is altered in KAI1/CD82-expressing cells, and 2) p130CAS-CrkII coupling is required for KAI1/CD82-mediated suppression of cell motility.
Vascular Biology Center and Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. xazhang@utmem.edu
Xin A
XA
Zhang
Bo
B
He
Bin
B
Zhou
Li
L
Liu
D015703:Antigens, CD; D002465:Cell Movement / Q000502:physiology; D050719:Crk-Associated Substrate Protein; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D051861:Kangai-1 Protein; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D009362:Neoplasm Metastasis / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D010750:Phosphoproteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000556:secondary*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014162:Transfection; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases / Q000378:metabolism
D015703:Antigens, CD; C493841:BCAR1 protein, human; C497688:CD82 protein, human; D050719:Crk-Associated Substrate Protein; D051861:Kangai-1 Protein; D008562:Membrane Glycoproteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050737:Proto-Oncogene Proteins c-crk; D011994:Recombinant Proteins; D050717:Retinoblastoma-Like Protein p130; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases