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A Heparin Binding Motif Rich in Arginine and Lysine is the Functional Domain of YKL-40

The heparin-binding glycoprotein YKL-40 (CHI3L1) is intimately associated with microvascularization in multiple human diseases including cancer and inflammation. However, the heparin-binding domain(s) pertinent to the angiogenic activity have yet been identified. YKL-40 harbors a consensus heparin-b...

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Detalles Bibliográficos
Autores principales: Ngernyuang, Nipaporn, Yan, Wei, Schwartz, Lawrence M., Oh, Dennis, Liu, Ying-bin, Chen, Hongzhuan, Shao, Rong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Neoplasia Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773473/
https://www.ncbi.nlm.nih.gov/pubmed/29274508
http://dx.doi.org/10.1016/j.neo.2017.11.011
Descripción
Sumario:The heparin-binding glycoprotein YKL-40 (CHI3L1) is intimately associated with microvascularization in multiple human diseases including cancer and inflammation. However, the heparin-binding domain(s) pertinent to the angiogenic activity have yet been identified. YKL-40 harbors a consensus heparin-binding motif that consists of positively charged arginine (R) and lysine (K) (RRDK; residues 144–147); but they don't bind to heparin. Intriguingly, we identified a separate KR-rich domain (residues 334–345) that does display strong heparin binding affinity. A short synthetic peptide spanning this KR-rich domain successfully competed with YKL-40 and blocked its ability to bind heparin. Three individual point mutations, where alanine (A) substituted for K or R (K337A, K342A, R344A), led to remarkable decreases in heparin-binding ability and angiogenic activity. In addition, a neutralizing anti-YKL-40 antibody that targets these residues and prevents heparin binding impeded angiogenesis in vitro. MDA-MB-231 breast cancer cells engineered to express ectopic K337A, K342A or R344A mutants displayed reduced tumor development and compromised tumor vessel formation in mice relative to control cells expressing wild-type YKL-40. These data reveal that the KR-rich heparin-binding motif is the functional heparin-binding domain of YKL-40. Our findings shed light on novel molecular mechanisms underlying endothelial cell angiogenesis promoted by YKL-40 in a variety of diseases.