Thy-1-Interacting Molecules and Cellular Signaling in Cis and Trans

Herrera-Molina, Rodrigo; Valdivia, Alejandra; Kong, Milene; Álvarez, Álvaro; Cárdenas, Areli; Quest, Andrew F. G.; Leyton, Lisette

doi:10.1016/b978-0-12-407695-2.00004-4

Cited by 43 publications

(58 citation statements)

References 229 publications

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“…As the respective binding sites for a 5 b 1 and Syn4 on Thy-1 are distinct 52 , the K562 cell may adhere to the Thy-1 probe via a bimolecular bond (Thy-1-a 5 b 1 or Thy-1-Syn4) and/or a trimolecular bond (Thy-1-a 5 b 1 þ Syn4), or their combinations. To determine the bond composition, we calculated the average numbers of Thy-1-a 5 b 1 or Thy-1-Syn4 bimolecular bonds (/n a5b1 S or /n Syn4 S) from the respective adhesion frequencies measured when Syn4 or a 5 b 1 was knocked down, respectively, and compared their sum with the average number of total bonds (/n total S) from the adhesion frequency measured with no treatments (Methods, equation (1)) 53 .…”

Section: Resultsmentioning

confidence: 99%

“…Although a distinct ligand from fibronectin, Thy-1 shares an important similarity in which binding sites to both integrin and syndecan are present and adjacent. Based on the predicted three-dimensional structure of Thy-1 (no crystal structure exists), the syndecan-binding site (REKRK) is positioned on the face of the molecule opposite the integrinbinding site (RLD) 52 . The trimolecular complex model (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

Fiore

Chen

et al. 2014

Nat Commun

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Cancer cell adhesion to the vascular endothelium is a critical step of tumour metastasis. Endothelial surface molecule Thy-1 (CD90) is implicated in the metastatic process through its interactions with integrins and syndecans. However, how Thy-1 supports cell-cell adhesion in a dynamic mechanical environment is not known. Here we show that Thy-1 supports b 1 integrin-and syndecan-4 (Syn4)-mediated contractility-dependent mechanosignalling of melanoma cells. At the single-molecule level, Thy-1 is capable of independently binding a 5 b 1 integrin and syndecan-4 (Syn4) receptors. However, in the presence of both a 5 b 1 and Syn4, the two receptors bind cooperatively to Thy-1, to form a trimolecular complex. This trimolecular complex displays a unique phenomenon we coin 'dynamic catch', characterized by abrupt bond stiffening followed by the formation of catch bonds, where force prolongs the bond lifetime. Thus, we reveal a new class of trimolecular interactions where force strengthens the synergistic binding of two co-receptors and modulates downstream mechanosignalling.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

Fiore

Chen

et al. 2014

Nat Commun

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“…For example, group B coxsackieviruses interact with the GPI-anchored protein decay-accelerating factor, which results in clustering of the protein and leads to virus delivery to tight junctions and subsequent endocytotic entry (97,98). Numerous studies have shown that cross-linking of THY-1 is essential for its role in signaling through Src and PI3K pathways (99,100). Src and PI3K are critical regulators of macropinocytosis (43,51).…”

Section: Discussionmentioning

confidence: 99%

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Fischer

Cohen

2016

J Virol

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Previously we showed that THY-1 has a critical role in the initial stage of infection of certain cell types with human cytomegalovirus (HCMV) and that THY-1 is important for HCMV-mediated activation of phosphatidylinositol 3-kinase (PI3K)/Akt during virus entry. THY-1 is known to interact with integrins and is a major cargo protein of clathrin-independent endocytic vesicles. Since macropinocytosis involves integrin signaling, is PI3K/Akt dependent, and is a clathrin-independent endocytic process, we determined whether THY-1 has a role in HCMV entry by macropinocytosis. Using electron microscopy in two cell lines that support HCMV infection in a THY-1-dependent manner, we found that HCMV enters these cells by a macropinocytosis-like process. THY-1 associated with HCMV virions on the cell surface and colocalized with virus inside macropinosomes. 5-(N-Ethyl-Nisopropyl)amiloride (EIPA) and soluble THY-1 blocked HCMV infection in the cell lines by >80% and 60%, respectively. HCMV entry into the cells triggered increased influx of extracellular fluid, a marker of macropinocytosis, and this increased fluid uptake was inhibited by EIPA and by soluble THY-1. Blocking actin depolymerization, Na ؉ /H ؉ exchange, PI3K, and Pak1 kinase, which are critical for macropinocytosis, impaired HCMV infection. Neither internalized HCMV virions nor THY-1 in virus-infected cells colocalized with transferrin as determined by confocal microscopy, indicating that clathrin-mediated endocytosis was not involved in THY-1-associated virus entry. These results suggest that HCMV has adapted to utilize THY-1, a cargo protein of clathrin-independent endocytotic vesicles, to facilitate efficient entry into certain cell types by a macropinocytosis-like process. IMPORTANCE Human cytomegalovirus (HCMV) infects over half of the population and is the most common infectious cause of birth defects.The virus is the most important infection occurring in transplant recipients. The mechanism of how HCMV enters cells is controversial. In this study, we show that THY-1, a cell surface protein that is critical for the early stage of entry of HCMV into certain cell types, contributes to virus entry by macropinocytosis. Our findings suggest that HCMV has adapted to utilize THY-1 to facilitate entry of HCMV into macropinosomes in certain cell types. Further knowledge about the mechanism of HCMV entry into cells may facilitate the development of novel inhibitors of virus infection. Human cytomegalovirus (HCMV) infects over half of the general population. While the infection is often asymptomatic when occurring in young children, it poses a serious health threat in transplant recipients and in immunocompromised individuals. HCMV is the most common infectious cause of birth defects. The virus infects a variety of host cells in vivo, including epithelial, endothelial, and muscle cells as well as fibroblasts. HCMV encodes multiple glycoproteins, some of which are not shared with other human herpesviruses, such as UL128, UL130, and UL131A. Other glycoproteins ar...

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“…Thy-1 is a small glycoprotein attached to the outer leaflet of the plasma membrane through a glycosylphosphatidylinositol anchor. The protein core is composed of 110 aa, with high carbohydrate modifications contributing to an additional 30% of Thy-1 mass (6). Due to its glycosyl-phosphatidylinositol anchor, Thy-1 is sensitive to cleavage by phosphatidylinositol-specific PLC.…”

Section: Structure Of Thy-1 and Signaling Cascadesmentioning

confidence: 99%

“…However, recent studies and analyses of Thy-1-deficient mice have revealed its significant functional impact beyond being a marker of certain cell types. The structure, expression, and function of Thy-1 on fibroblasts, neurons, endothelial cells, and thymocytes have already been excellently reviewed (4)(5)(6)(7)(8)(9)(10). For many years, Thy-1 has been used as a marker to identify mesenchymal stromal cells (MSCs).…”

mentioning

confidence: 99%

Thy‐1: more than a marker for mesenchymal stromal cells

Saalbach

Anderegg

2019

FASEB j.

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Balanced differentiation of mesenchymal stromal cells (MSCs) into osteoblasts and adipocytes is essential for healthy bone and fat homeostasis. A disturbed balance of MSC differentiation results in bone loss and increased adipogenesis as observed in several human conditions, such as osteoporosis, obesity, and aging. This reflects the importance of MSC fate decision. Therefore, it is important to identify factors that regulate the balance between osteogenic and adipogenic differentiation of MSCs so as to identify new targets to improve bone formation in osteoporosis and control adipose tissue development. There is accumulating evidence that thymus cell antigen 1 (Thy‐1), also known as CD90, expressed on MSCs, plays a critical role in the fate decision of MSCs. Recently, Thy‐1 has been shown to promote osteogenic differentiation of MSCs and thus bone formation while inhibiting adipogenic differentiation and restricting adipose tissue accumulation. The clinical importance of these findings was validated by the detection of reduced serum soluble Thy‐1 in patients with disturbed bone remodeling. In this review, we aim to summarize data on the impact of Thy‐1 on the control of MSC differentiation and its consequences for bone and fat formation.—Saalbach, A., Anderegg, U. Thy‐1: more than a marker for mesenchymal stromal cells. FASEB J. 33, 6689–6696 (2019). http://www.fasebj.org

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Thy-1-Interacting Molecules and Cellular Signaling in Cis and Trans

Cited by 43 publications

References 229 publications

Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

Dynamic catch of a Thy-1–α5β1+syndecan-4 trimolecular complex

Cell Surface THY-1 Contributes to Human Cytomegalovirus Entry via a Macropinocytosis-Like Process

Thy‐1: more than a marker for mesenchymal stromal cells

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