title: Podocalyxin EBP50 ezrin molecular complex enhances the metastatic potential of renal cell carcinoma through recruiting Rac1 guanine nucleotide exchange factor ARHGEF7.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Taipei Medical University-Shuang Ho Medical Center, Taipei, Taiwan.
authors.forename: Yung-Ho
authors.initials: YH
authors.lastname: Hsu
authors.forename: Wei-Ling
authors.initials: WL
authors.lastname: Lin
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Hou
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.forename: Chia-Tung
authors.initials: CT
authors.lastname: Shun
authors.forename: Chi-Ling
authors.initials: CL
authors.lastname: Chen
authors.forename: Yih-Yiing
authors.initials: YY
authors.lastname: Wu
authors.forename: Jen-Yau
authors.initials: JY
authors.lastname: Chen
authors.forename: Tso-Hsiao
authors.initials: TH
authors.lastname: Chen
authors.forename: Tzuu-Shuh
authors.initials: TS
authors.lastname: Jou
mesh_terms: 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
chemical_list: 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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