title: Structure-function approach identifies a COOH-terminal domain that mediates heparanase signaling.
abstract: Heparanase is an endo-beta-d-glucuronidase capable of cleaving heparan sulfate, activity that is strongly implicated in cellular invasion associated with tumor metastasis, angiogenesis, and inflammation. In addition, heparanase was noted to exert biological functions apparently independent of its enzymatic activity, enhancing the phosphorylation of selected protein kinases and inducing gene transcription. A predicted three-dimensional structure of constitutively active heparanase clearly delineates a TIM-barrel fold previously anticipated for the enzyme. Interestingly, the model also revealed the existence of a COOH-terminal domain (C-domain) that apparently is not an integral part of the TIM-barrel fold. We provide evidence that the C-domain is critical for heparanase enzymatic activity and secretion. Moreover, the C-domain was found to mediate nonenzymatic functions of heparanase, facilitating Akt phosphorylation, cell proliferation, and tumor xenograft progression. These findings support the notion that heparanase exerts enzymatic activity-independent functions, and identify, for the first time, a protein domain responsible for heparanase-mediated signaling. Inhibitors directed against the C-domain, combined with inhibitors of heparanase enzymatic activity, are expected to neutralize heparanase functions and to profoundly affect tumor growth, angiogenesis, and metastasis.
authors.affiliation: Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel.
authors.forename: Liat
authors.initials: L
authors.lastname: Fux
authors.forename: Nir
authors.initials: N
authors.lastname: Feibish
authors.forename: Victoria
authors.initials: V
authors.lastname: Cohen-Kaplan
authors.forename: Svetlana
authors.initials: S
authors.lastname: Gingis-Velitski
authors.forename: Sari
authors.initials: S
authors.lastname: Feld
authors.forename: Chen
authors.initials: C
authors.lastname: Geffen
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Neta
authors.initials: N
authors.lastname: Ilan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D008958:Models, Molecular; D009374:Neoplasms, Experimental / Q000209:etiology; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D051057:Proto-Oncogene Proteins c-akt; D000099175:Heparanase