Syndecan Transmembrane Domain Specifically Regulates Downstream Signaling Events of the Transmembrane Receptor Cytoplasmic Domain.

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

doi:10.3390/ijms22157918

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 unknown. 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 effects, 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, comprising 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 corresponding 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.

Highlights

Extracellular ligands bind to the extracellular domain of cell surface membrane receptors to initiate a transmembrane domain (TMD)-mediated receptor transition
We have shown the importance of the functional dimerization of TMD in syndecans using various cell lines [8,9], there was no direct evidence showing that this
TMD-induced dimerization correlates with syndecan function in an organism

Summary

Introduction

Extracellular ligands bind to the extracellular domain of cell surface membrane receptors (e.g., growth factor receptors) to initiate a transmembrane domain (TMD)-mediated receptor transition. During this process, the TMD and the cytoplasmic domain cluster to trigger the specific intracellular signaling events that regulate various cell functions, such as cell proliferation [1]. Phosphorylation at different tyrosine residues will induce specific interactions of the PDGFR cytoplasmic domain with intracellular adapter molecules containing Src homology domains, which will regulate downstream signal transduction [2]. The functions of the PDGFR cytoplasmic domain are relatively well known, it is not clear how the TMD performs its specific regulatory roles for most cell surface receptors

Methods

Results

Conclusion