Requirement of the conserved, hydrophobic C-terminus region for the activation of heparanase.
Heparanase is an endo-beta-D-glucuronidase responsible for the cleavage of heparan sulfate, participating in extracellular matrix degradation and remodeling. Heparanase activity is well correlated with the potential for metastasis and angiogenesis in a large number of tumor-derived cell types, directly implicating the involvement of heparanase in tumor progression. Here, we provide the first evidence that the hydrophobic C-terminus region of heparanase has specific roles in intracellular trafficking, secretion, activation, and heparanase-mediated tumor cell migration. Furthermore, partial deletion of this hydrophobic C-terminus region, substitution within the hydrophobic C-terminus region to hydrophilic amino acids, and experiments of single amino acid mutations further point out the importance of the hydrophobic C-terminus region. Therefore, our findings suggest that the hydrophobic C-terminus region of heparanase is a determinant for its intracellular trafficking to the Golgi apparatus, followed by secretion, activation, and tumor cell migration.
Lai
Ngit Shin
NS
Antibiotics Laboratory, Advanced Science Institute, RIKEN, Saitama 351-0198, Japan.
Simizu
Siro
S
Morisaki
Daiki
D
Muroi
Makoto
M
Osada
Hiroyuki
H
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D017124:Conserved Sequence / Q000502:physiology*; D004789:Enzyme Activation / Q000502:physiology; D019143:Evolution, Molecular; D005109:Extracellular Matrix / Q000201:enzymology*; D005966:Glucuronidase / Q000737:chemistry / Q000378:metabolism*; D006056:Golgi Apparatus / Q000201:enzymology / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D017384:Sequence Deletion; D014407:Tumor Cells, Cultured; D000099175:Heparanase
D005966:Glucuronidase; D006497:Heparan Sulfate; D000099175:Heparanase