The Cardiac Syndecan-2 Interactome

Abstract

The extracellular matrix (ECM) is important in cardiac remodeling and syndecans have gained increased interest in this process due to their ability to convert changes in the ECM to cell signaling. In particular, syndecan-4 has been shown to be important for cardiac remodeling, whereas the role of its close relative syndecan-2 is largely unknown in the heart. To get more insight into the role of syndecan-2, we here sought to identify interaction partners of syndecan-2 in rat left ventricle. By using three different affinity purification methods combined with mass spectrometry (MS) analysis, we identified 30 novel partners and 9 partners previously described in the literature, which together make up the first cardiac syndecan-2 interactome. Eleven of the novel partners were also verified in HEK293 cells (i.e., AP2A2, CAVIN2, DDX19A, EIF4E, JPH2, MYL12A, NSF, PFDN2, PSMC5, PSMD11, and RRAD). The cardiac syndecan-2 interactome partners formed connections to each other and grouped into clusters mainly involved in cytoskeletal remodeling and protein metabolism, but also into a cluster consisting of a family of novel syndecan-2 interaction partners, the CAVINs. MS analyses revealed that although syndecan-2 was significantly enriched in fibroblast fractions, most of its partners were present in both cardiomyocytes and fibroblasts. Finally, a comparison of the cardiac syndecan-2 and-4 interactomes revealed surprisingly few protein partners in common.

Meta‐analysis reveals differential gene expression in tetralogy of Fallot versus controls

“…Relevant genes identified as some of the top upregulated and downregulated in our dataset include MYL12A, FBXO32, NR2F2, and PTGES, though FBXO32 and PTGES show the most promise as potential targets for screening, prevention, and/or treatment strategies for TOF. MYL12a is a partner of syndecan‐2 interactome, which is upregulated during development and suspected to be involved in fibroblast contractility and cardiac fibrosis (Mathiesen et al, 2020). Syndecans are hypothesized to play a role in cardiac remodeling via their alterations of and interaction with the extracellular matrix (Mathiesen et al, 2020).…”

“…MYL12a is a partner of syndecan-2 interactome, which is upregulated during development and suspected to be involved in fibroblast contractility and cardiac fibrosis (Mathiesen et al, 2020). Syndecans are hypothesized to play a role in cardiac remodeling via their alterations of and interaction with the extracellular matrix (Mathiesen et al, 2020). MYL12a specifically has been noted to be involved in focal adhesion, leukocyte transendothelial migration, and regulation of the actin cytoskeleton (Mathiesen et al, 2020).…”

“…Syndecans are hypothesized to play a role in cardiac remodeling via their alterations of and interaction with the extracellular matrix (Mathiesen et al, 2020). MYL12a specifically has been noted to be involved in focal adhesion, leukocyte transendothelial migration, and regulation of the actin cytoskeleton (Mathiesen et al, 2020). MYL12a has been reported to be upregulated in patients with Pompe disease as well, which is characterized by cardiomyocyte hypertrophy (Karada g Gürel & Gürel, 2022).…”

Role of adaptin protein complexes in intracellular trafficking and their impact on diseases

“…AP2A2 has a partially non-redundant function with AP2A1 owing to its unique peroxisome proliferator-activated receptor (PPAR) α responding domain, which increases fatty acid oxidization in the adipose tissue [81] by interacting with syndecan-2, a mediator of extracellular matrix (ECM) signaling in cardiac tissue [82]. Listeria monocytogenes bacteria-induced cytotoxicity was reportedly inhibited by the binding of bacterial proteins to AP2A2 in a pathway enabling bacterial growth in host cells [83].…”

“…Both AP2A1 and AP2A2 were reported to confer resistance to erlotinib, an anti-cancer drug, in lung cancer cells [ 78 ]; interact with Shc, an SH2-containing proto-oncogene involved in growth factor signaling in mammalian cancer cells [ 79 ]; and function in hemopoietic stem cell development [ 80 ]. AP2A2 has a partially non-redundant function with AP2A1 owing to its unique peroxisome proliferator-activated receptor (PPAR) α responding domain, which increases fatty acid oxidization in the adipose tissue [ 81 ] by interacting with syndecan-2, a mediator of extracellular matrix (ECM) signaling in cardiac tissue [ 82 ]. Listeria monocytogenes bacteria-induced cytotoxicity was reportedly inhibited by the binding of bacterial proteins to AP2A2 in a pathway that enable bacterial growth in host cells [ 83 ].…”