title: Heat shock cognate 70 regulates the translocation and angiogenic function of nucleolin.
abstract: OBJECTIVE
  Cell surface nucleolin (NCL) plays fundamental roles in tumor angiogenesis. However, the mechanism underlying its surface translocation remains obscure. The present study discovered that heat shock cognate 70 (Hsc70) is essential in both the surface translocation and the angiogenic function of NCL.
  
  
  RESULTS
  We identified that Hsc70 interacted with NCL in endothelial cells via the peptide-binding domain of Hsc70 and the RNA-binding domain of NCL. Functional knockdown of Hsc70 remarkably inhibited the expression of surface NCL, which was rescued by wild-type Hsc70 rather than its truncations. Phosphorylation of NCL by either protein kinase C-ξ or casein kinase 2 mediated its interaction with Hsc70 and the surface expression. Hsc70 regulated NCL translocation via stabilizing NCL and enhancing its interaction with nonmuscle myosin heavy chain 9. Moreover, Hsc70 was associated with NCL-induced endothelial cell migration and tubule formation in vitro and angiogenesis in both matrigel plugs and xenograft tumors. Tissue array analysis revealed that the expression levels of NCL and Hsc70 were intimately correlated in human lung adenocarcinomas.
  
  
  CONCLUSIONS
  Our study demonstrates that Hsc70 is a prerequisite for the surface translocation and angiogenic function of NCL, which suggests strategies to target both Hsc70 and NCL for more effective antiangiogenic therapies.
authors: National Engineering Laboratory for Antitumor Protein Therapeutics; Beijing Key Laboratory for Protein Therapeutics, Beijing, China.
authors: Yanping
authors: Y
authors: Ding
authors: Nan
authors: N
authors: Song
authors: Chang
authors: C
authors: Liu
authors: Ting
authors: T
authors: He
authors: Wei
authors: W
authors: Zhuo
authors: Xiaoli
authors: X
authors: He
authors: Yang
authors: Y
authors: Chen
authors: Xiaomin
authors: X
authors: Song
authors: Yan
authors: Y
authors: Fu
authors: Yongzhang
authors: Y
authors: Luo
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001665:Binding Sites; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D050883:HSC70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D018995:Myosin Heavy Chains / Q000378:metabolism; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D055550:Protein Stability; D021381:Protein Transport; D011760:Pyrrolidinones / Q000494:pharmacology; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D046888:Tissue Array Analysis; D014162:Transfection; D023041:Xenograft Model Antitumor Assays; D000097796:Nucleolin
chemical_list: D001559:Benzhydryl Compounds; D047390:Casein Kinase II; D050883:HSC70 Heat-Shock Proteins; D018995:Myosin Heavy Chains; D010750:Phosphoproteins; D051744:Protein Kinase C-epsilon; D011760:Pyrrolidinones; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C494371:HSPA8 protein, human; C410027:KNK 437