RT Journal Article
SR Electronic
T1 MST1R/RON and EGFR in a complex with syndecans sustain carcinoma S-phase progression by preventing p38MAPK activation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 252742
DO 10.1101/252742
A1 DeannaLee M. Beauvais
A1 Kristin Short
A1 Noah Stueven
A1 Scott E. Nelson
A1 Denis Lee
A1 Oisun Jung
A1 Richard A. Anderson
A1 Paul F. Lambert
A1 Alan C. Rapraeger
YR 2018
UL http://biorxiv.org/content/early/2018/01/24/252742.abstract
AB Syndecan-4 (Sdc4) organizes a complex of receptors consisting of its homologue, Sdc2, the receptor tyrosine kinases EGFR and MST1R/RON, and the laminin-binding α3β1 and α6β4 integrins that depends on a docking site within its extracellular domain. A peptide mimetic of the extracellular docking site, synstatin-EGFR (SSTNEGFR), disrupts the receptor complex and prevents the invasion of non-transformed or carcinoma cells that relies on active EGFR. However, the peptide also prevents DNA replication that relies on active MST1R/RON and c-Abl kinase within the complex, resulting in rapid S-phase arrest of head & neck (HN) and breast carcinoma cells. SSTNEGFR does not affect DNA replication in non-transformed oral or breast epithelial cells, but it does block their EGF-dependent invasion. Although EGFR is required as a component of the complex, its kinase activity is not required to sustain S-phase progression in the carcinoma cells, perhaps explaining why many HN and breast carcinomas that overexpress EGFR are nonetheless refractory to EGFR inhibitors. The syndecan-organized receptor complex (Sdc:RTK:ITG complex) appears to suppress stress signals that would otherwise disrupt the replisome engaged in DNA synthesis. SSTNEGFR-treatment of carcinoma cells, or normal oral epithelial cells expressing stress-inducing HPV oncogenes, causes rapid activation of the p38 stress MAPK leading to loss of PCNA from the chromatin and cessation of DNA synthesis. This arrest is independent of the common DNA damage response (DDR) known to activate an S-phase checkpoint, revealing a novel arrest mechanism and a novel receptor complex that is activated on tumor cells to suppress stress-induced proliferation arrest.