Syndecan transmembrane domain specifically regulates downstream signaling events of the transmembrane receptor cytoplasmic domain

Jisun Hwang, Bohee Jang, Ayoung Kim, Yejin Lee, Joonha Lee, Chungho Kim, Jinmahn Kim, Kyeong Min Moon, Kyuhyung Kim, Ram Wagle, Young Han Song, Eok Soo Oh

Research output: Contribution to journalArticlepeer-review

Abstract

Despite the known importance of the transmembrane domain (TMD) of syndecan receptors in cell adhesion and signaling, the molecular basis for syndecan TMD function remains un-known. Using in vivo invertebrate models, we found that mammalian syndecan-2 rescued both the guidance defects in C. elegans hermaphrodite-specific neurons and the impaired development of the midline axons of Drosophila caused by the loss of endogenous syndecan. These compensatory ef-fects, however, were reduced significantly when syndecan-2 dimerization-defective TMD mutants were introduced. To further investigate the role of the TMD, we generated a chimera, 2eTPC, com-prising the TMD of syndecan-2 linked to the cytoplasmic domain of platelet-derived growth factor receptor (PDGFR). This chimera exhibited SDS-resistant dimer formation that was lost in the corre-sponding dimerization-defective syndecan-2 TMD mutant, 2eT(GL)PC. Moreover, 2eTPC specifically enhanced Tyr 579 and Tyr 857 phosphorylation in the PDGFR cytoplasmic domain, while the TMD mutant failed to support such phosphorylation. Finally, 2eTPC, but not 2eT(GL)PC, induced phosphorylation of Src and PI3 kinase (known downstream effectors of Tyr 579 phosphorylation) and promoted Src-mediated migration of NIH3T3 cells. Taken together, these data suggest that the TMD of a syndecan-2 specifically regulates receptor cytoplasmic domain function and subsequent downstream signaling events controlling cell behavior.

Original languageEnglish
Article number7918
JournalInternational Journal of Molecular Sciences
Volume22
Issue number15
DOIs
StatePublished - 1 Aug 2021

Keywords

  • PDGFR
  • Signal transduction
  • Syndecan
  • Transmembrane domain

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