Podocalyxin EBP50 ezrin molecular complex enhances the metastatic potential of renal cell carcinoma through recruiting Rac1 guanine nucleotide exchange factor ARHGEF7.
Podocalyxin was initially identified in glomerular podocytes to critically maintain the structural and functional integrity of the glomerular ultrafiltrative apparatus. Lately, it has emerged as a malignant marker in tumors arising from a variety of tissue origins. By immunohistochemistry, we identified that 9.6% of renal cell carcinoma patients overexpress this protein. This subset of patients had significantly shorter disease-specific and overall survivals, and, importantly, we established podocalyxin overexpression as an independent prognostic factor for latent distant metastasis with multivariate analysis. Podocalyxin down-regulation by small interfering RNA led to defective migration in model renal tubular cells, which was corrected by re-expression of podocalyxin. The activity of the small GTPase Rac1, a well-characterized modulator of cell migration, was diminished by podocalyxin knock-down. Conversely, podocalyxin overexpression in human embryonic kidney cells up-regulated Rac1 activity, which depended on a complex formed by podocalyxin, ERM-binding phosphoprotein 50, ezrin, and ARHGEF7, a Rac1 activator. Therefore, podocalyxin can serve as a biomarker to identify renal cell carcinoma patients with higher metastatic potential for more aggressive intervention at earlier clinical stages.
Hsu
Yung-Ho
YH
Department of Internal Medicine, Taipei Medical University-Shuang Ho Medical Center, Taipei, Taiwan.
Lin
Wei-Ling
WL
Hou
Yi-Ting
YT
Pu
Yeong-Shiau
YS
Shun
Chia-Tung
CT
Chen
Chi-Ling
CL
Wu
Yih-Yiing
YY
Chen
Jen-Yau
JY
Chen
Tso-Hsiao
TH
Jou
Tzuu-Shuh
TS
D000328:Adult; D000368:Aged; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D004789:Enzyme Activation; D005260:Female; D055785:Gene Knockdown Techniques; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D046912:Multiprotein Complexes / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D064067:Rho Guanine Nucleotide Exchange Factors; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D000099149:Ezrin
D003598:Cytoskeletal Proteins; D020662:Guanine Nucleotide Exchange Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D064067:Rho Guanine Nucleotide Exchange Factors; D012795:Sialoglycoproteins; D017923:Sodium-Hydrogen Exchangers; D020830:rac1 GTP-Binding Protein; D000099149:Ezrin; C001643:podocalyxin; C093376:sodium-hydrogen exchanger regulatory factor
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