<scp>CD</scp>146 interacts with galectin‐3 to mediate endothelial cell migration

Zhang, Zhongyu; Zheng, Yi; Wang, Hao; Zhou, Yifa; Tai, Guihua

doi:10.1002/1873-3468.13083

Cited by 20 publications

(15 citation statements)

References 38 publications

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“…It has been reported that domain 5 of the CD146 protein contains poly-N-acetyllactosamine sites, namely, N418, N449, and N544, and that the glycosylation of CD146 promotes the binding of CD146 to Galectin-3 and Galectin-1. [41][42][43][44] We suggest that the glycosylation of CD146 domain 5 also contributes to the binding of CD146 to Galectin-9, which is supported by the following evidence: A functional antibody against CD146, AA98, has been reported to act at domains 4-5 of CD146. 45 In our present study, treatment with AA98 significantly reduced the interaction of CD146 with Galectin-9.…”

Section: Discussionsupporting

confidence: 59%

Targeting the CD146/Galectin-9 axis protects the integrity of the blood–brain barrier in experimental cerebral malaria

et al. 2020

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Cerebral malaria (CM) is a life-threatening diffuse encephalopathy caused by Plasmodium falciparum, in which the destruction of the blood–brain barrier (BBB) is the main cause of death. However, increasing evidence has shown that antimalarial drugs, the current treatment for CM, do little to protect against CM-induced BBB damage. Therefore, a means to alleviate BBB dysfunction would be a promising adjuvant therapy for CM. The adhesion molecule CD146 has been reported to be expressed in both endothelial cells and proinflammatory immune cells and mediates neuroinflammation. Here, we demonstrate that CD146 expressed on BBB endothelial cells but not immune cells is a novel therapeutic target in a mouse model of experimental cerebral malaria (eCM). Endothelial CD146 is upregulated during eCM development and facilitates the sequestration of infected red blood cells (RBCs) and/or proinflammatory lymphocytes in CNS blood vessels, thereby promoting the disruption of BBB integrity. Mechanistic studies showed that the interaction of CD146 and Galectin-9 contributes to the aggregation of infected RBCs and lymphocytes. Deletion of endothelial CD146 or treatment with the anti-CD146 antibody AA98 prevents severe signs of eCM, such as limb paralysis, brain vascular leakage, and death. In addition, AA98 combined with the antiparasitic drug artemether improved the cognition and memory of mice with eCM. Taken together, our findings suggest that endothelial CD146 is a novel and promising target in combination with antiparasitic drugs for future CM therapies.

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Section: Discussionsupporting

confidence: 59%

Targeting the CD146/Galectin-9 axis protects the integrity of the blood–brain barrier in experimental cerebral malaria

et al. 2020

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“…These findings provide a better understanding of how Galectin-3 interacts with cell-surface receptors to mediate endothelial cell migration and the secretion of cytokines. 123,124 The endothelial galectins are confined to four family members, i.e., Galectin-1, -3, -8, and -9, which contribute to tumor angiogenesis. 92 Tumor-induced angiogenesis is a pathologic condition in which tumor cells secrete growth factors, such as VEGFs, to promote the growth of new blood vessels.…”

Section: Galectin-3mentioning

confidence: 99%

“…These findings provide a better understanding of how Galectin-3 interacts with cell-surface receptors to mediate endothelial cell migration and the secretion of cytokines. 123 , 124 …”

Section: Cd146 Is the Receptor Of Proteins In Relation To The Ecmmentioning

confidence: 99%

CD146, from a melanoma cell adhesion molecule to a signaling receptor

Wang

Zhang

et al. 2020

Sig Transduct Target Ther

101

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CD146 was originally identified as a melanoma cell adhesion molecule (MCAM) and highly expressed in many tumors and endothelial cells. However, the evidence that CD146 acts as an adhesion molecule to mediate a homophilic adhesion through the direct interactions between CD146 and itself is still lacking. Recent evidence revealed that CD146 is not merely an adhesion molecule, but also a cellular surface receptor of miscellaneous ligands, including some growth factors and extracellular matrixes. Through the bidirectional interactions with its ligands, CD146 is actively involved in numerous physiological and pathological processes of cells. Overexpression of CD146 can be observed in most of malignancies and is implicated in nearly every step of the development and progression of cancers, especially vascular and lymphatic metastasis. Thus, immunotherapy against CD146 would provide a promising strategy to inhibit metastasis, which accounts for the majority of cancer-associated deaths. Therefore, to deepen the understanding of CD146, we review the reports describing the newly identified ligands of CD146 and discuss the implications of these findings in establishing novel strategies for cancer therapy.

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“…Sample preparation for MS spectrometry was performed as previously reported with minor modifications [62]. Briefly, following the PPi hydrolysis reaction with 100 μg AbPPase, samples were dissolved in 50 mM NH 4 HCO 3 buffer, and solely the AbPPase sample was used as a negative control in this mass spectroscopy study.…”

Section: Methodsmentioning

confidence: 99%

Crystal Structures of Pyrophosphatase from Acinetobacter baumannii: Snapshots of Pyrophosphate Binding and Identification of a Phosphorylated Enzyme Intermediate

Wang

Yang³

et al. 2019

IJMS

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All living things have pyrophosphatases that hydrolyze pyrophosphate and release energy. This energetically favorable reaction drives many energetically unfavorable reactions. An accepted catalytic model of pyrophosphatase shows that a water molecule activated by two divalent cations (M1 and M2) within the catalytic center can attack pyrophosphate in an SN2 mechanism and thus hydrolyze the molecule. However, our co-crystal structure of Acinetobacter baumannii pyrophosphatase with pyrophosphate shows that a water molecule from the solvent may, in fact, be the actual catalytic water. In the co-crystal structure of the wild-type pyrophosphatase with pyrophosphate, the electron density of the catalytic centers of each monomer are different from one another. This indicates that pyrophosphates in the catalytic center are dynamic. Our mass spectroscopy results have identified a highly conserved lysine residue (Lys30) in the catalytic center that is phosphorylated, indicating that the enzyme could form a phosphoryl enzyme intermediate during hydrolysis. Mutation of Lys30 to Arg abolished the activity of the enzyme. In the structure of the apo wild type enzyme, we observed that a Na+ ion is coordinated by residues within a loop proximal to the catalytic center. Therefore, we mutated three key residues within the loop (K143R, P147G, and K149R) and determined Na+ and K+-induced inhibition on their activities. Compared to the wild type enzyme, P147G is most sensitive to these cations, whereas K143R was inactive and K149R showed no change in activity. These data indicate that monovalent cations could play a role in down-regulating pyrophosphatase activity in vivo. Overall, our results reveal new aspects of pyrophosphatase catalysis and could assist in the design of specific inhibitors of Acinetobacter baumannii growth.

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CD146 interacts with galectin‐3 to mediate endothelial cell migration

Cited by 20 publications

References 38 publications

Targeting the CD146/Galectin-9 axis protects the integrity of the blood–brain barrier in experimental cerebral malaria

Targeting the CD146/Galectin-9 axis protects the integrity of the blood–brain barrier in experimental cerebral malaria

CD146, from a melanoma cell adhesion molecule to a signaling receptor

Crystal Structures of Pyrophosphatase from Acinetobacter baumannii: Snapshots of Pyrophosphate Binding and Identification of a Phosphorylated Enzyme Intermediate

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