NDLI: NOVEL SYNSTATINS PREVENT KINASE CAPTURE AND INHIBIT α6β4-INTEGRIN-DEPENDENT EPITHELIAL CELL MOTILITY*

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Wang, Haiyao Jin, Haining Rapraeger, Alan C.
Description	Author Affiliation: Wang H ( From the Department of Human Oncology and.); Jin H ( From the Department of Human Oncology and.); Rapraeger AC ( From the Department of Human Oncology and the University of Wisconsin Carbone Cancer Center, Wisconsin Institutes for Medical Research, University of Wisconsin-Madison, Madison, Wisconsin 53705 rapraeger@humonc.wisc.edu.)
Abstract	The α6β4 integrin is known to associate with receptor tyrosine kinases when engaged in epithelial wound healing and in carcinoma invasion and survival. Prior work has shown that HER2 associates with α6β4 integrin and syndecan-1 (Sdc1), in which Sdc1 engages the cytoplasmic domain of the β4 integrin subunit allowing HER2-dependent motility and carcinoma cell survival. In contrast, EGFR associates with Sdc4 and the α6β4 integrin, and EGFR-dependent motility depends on cytoplasmic engagement of β4 integrin with Sdc4. However, how HER2 and EGFR assimilate into a complex with the syndecans and integrin, and why kinase capture is syndecan-specific has remained unknown. In the present study, we demonstrate that HER2 is captured via a site, comprised of amino acids 210–240, in the extracellular domain of human Sdc1, and EGFR is captured via an extracellular site comprised of amino acids 87–131 in human Sdc4. Binding assays using purified recombinant proteins demonstrate that the interaction between the EGFR family members and the syndecans is direct. The α3β1 integrin, which is responsible for the motility of the cells, is captured at these sites as well. Peptides based on the interaction motifs in Sdc1 and Sdc4, called synstatins $(SSTN_{210–240}$ and $SSTN_{87–131})$ competitively displace the receptor tyrosine kinase and α3β1 integrin from the syndecan with an $IC_{50}$ of 100–300 nm. The syndecans remain anchored to the α6β4 integrin via its cytoplasmic domain, but the activation of cell motility is disrupted. These novel SSTN peptides are potential therapeutics for carcinomas that depend on these HER2- and EGFR-coupled mechanisms for their invasion and survival.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	43
Volume Number	290
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2015-10-23
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Cell Movement Integrin Alpha3beta1 Metabolism Integrin Alpha6beta4 Receptor, Epidermal Growth Factor Receptor, ErbB-2 Syndecan-1 Syndecan-4 Amino Acid Sequence Animals Binding Sites Cell Line Epithelial Cells Molecular Sequence Data Sequence Homology, Amino Acid Chemistry Research Support, N.I.H., Extramural Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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