C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation - PubMed (original) (raw)

Review

. 2019 Sep;286(17):3299-3332.

doi: 10.1111/febs.14985. Epub 2019 Jul 29.

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Review

C-type lectin domain group 14 proteins in vascular biology, cancer and inflammation

Kabir A Khan et al. FEBS J. 2019 Sep.

Abstract

The C-type lectin domain (CTLD) group 14 family of transmembrane glycoproteins consist of thrombomodulin, CD93, CLEC14A and CD248 (endosialin or tumour endothelial marker-1). These cell surface proteins exhibit similar ectodomain architecture and yet mediate a diverse range of cellular functions, including but not restricted to angiogenesis, inflammation and cell adhesion. Thrombomodulin, CD93 and CLEC14A can be expressed by endothelial cells, whereas CD248 is expressed by vasculature associated pericytes, activated fibroblasts and tumour cells among other cell types. In this article, we review the current literature of these family members including their expression profiles, interacting partners, as well as established and speculated functions. We focus primarily on their roles in the vasculature and inflammation as well as their contributions to tumour immunology. The CTLD group 14 family shares several characteristic features including their ability to be proteolytically cleaved and engagement of some shared extracellular matrix ligands. Each family member has strong links to tumour development and in particular CD93, CLEC14A and CD248 have been proposed as attractive candidate targets for cancer therapy.

Keywords: C-type lectin; CD248; CD93; CLEC14A; cancer; extracellular matrix; group XIV; immuno-oncology; thrombomodulin; vascular targeting.

© 2019 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

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Conflict of interest statement

KAK and RB are inventors on patents WO/2016/116760 entitled ‘Inhibitors of the interaction between CLEC14A and Multimerin‐2 for inhibition of angiogenesis’ and the related filed patents GB1612860.5, GB1612534.6 and GB1702926.5.

Figures

Figure 1

Figure 1

CTLD

group 14 family proteins. Schematic diagrams of the

CTLD

group 14 family proteins. Each protein is drawn to relative scale based on primary amino acid sequence length. The

CTLD

is shown in red, the sushi in blue and the

EGF

repeats in green.

Figure 2

Figure 2

Alignments of

CTLD

group 14 family members based on amino acid sequence. Amino acid alignments of the whole primary sequence of each human family member using PRALINE 229. The following protein sequences were used thrombomodulin (

http://www.uniprot.org/uniprot/P07204

),

CD

93 (

http://www.uniprot.org/uniprot/Q9NPY3

),

CLEC

14A (

http://www.uniprot.org/uniprot/Q86T13

) and

CD

248 (

http://www.uniprot.org/uniprot/Q9HCU0

).

Figure 3

Figure 3

Schematic of thrombomodulin protein structure with ligand binding partners. Thrombomodulin

CTLD

has been shown to interact with fibronectin,

HMGB

1, Kringle 1–5, Lewis Y antigen and

HSP

70‐1. The

CTLD

may be proteolytically cleaved by an as yet unidentified

MMP

. Thrombin binds to the 5th and 6th

EGF

domains, this binding is in competition with Ang1 and/or Ang2.

RHBDL

2 can cleave the whole ECD of thrombomodulin as can neutrophil elastase, cathepsin G and proteinase 3. The cytoplasmic tail binds to ezrin which in turn links thrombomodulin to the actin cytoskeleton.

Figure 4

Figure 4

Schematic of

CD

248 structure with ligand binding partners.

CD

248

CTLD

binds to fibronectin, Mac‐2

BP

, Collagens I and

IV

and

MMRN

2. There are currently no known direct intracellular interaction partners for

CD

Figure 5

Figure 5

Schematic of

CD

93 structure with ligand binding partners.

CD

93

CTLD

binds to

MMRN

2. The whole ECD has been shown to be cleaved by an as yet unidentified metalloproteinase. The intracellular cytoplasmic domain binds to moesin which in turn links

CD

93 to the actin cytoskeleton. The cytoplasmic domain also binds to Cbl and

GIPC

1 and src.

Figure 6

Figure 6

Schematic of

CLEC

14A protein with ligand binding partners.

CLEC

14A

CTLD

binds to

MMRN

2 and to

HSP

70‐1A. The whole ECD can be cleaved by

RHBDL

2. There are currently no known direct intracellular partners for

CLEC

14A.

Figure 7

Figure 7

Expression of

CTLD

group 14 family members in mouse tissues. The Tabula Muris database was used to determine which mouse cell types expressed each

CTLD

group 14 family gene from data acquired through fluorescence activated cell sorting and single‐cell gene expression analysis. The t‐

SNE

plot at the top displays annotations of each cell type and shows a legend of colours corresponding to which organ or tissue type that cell was from. The lower t‐

SNE

plots display in which cell types each family member was expressed (purple), ln(1 +

CPM

) is the natural logarithm of counts per million + 1.

Figure 8

Figure 8

Endothelial expression of

CTLD

group 14 family members in mouse tissues. (A) The Tabula Muris database was used to create t‐

SNE

plots of all endothelial cells from different organs as well as brain pericytes. The t‐

SNE

plot at the top left displays a legend of colours corresponding to which organ or tissue type that cell was from. Expression of each

CTLD

group 14 family member within these cell types are displayed as t‐

SNE

plots. (B) Single‐cell sequencing data analysed as fragments per kilobase million was used to compare

CD

93 and

CLEC

14A expression in different endothelial cells from different organs. Wilcoxon statistical test was used to compare ****P ≤ 0.0001 Aorta

EC

s n = 262, Brain nonmyeloid

EC

n = 1250, Diaphragm

EC

n = 154, Fat

EC

n = 1180, Heart

EC

n = 2274, Heart endocardial cell n = 350, Kidney

EC

n = 80, Limb Muscle

EC

n = 258, Liver

EC

n = 392, Lung

EC

n = 1476, Mammary gland

EC

n = 98, Pancreas

EC

n = 98, Trachea

EC

n = 66. (C) t‐

SNE

plots of lung endothelium alone were created which revealed the presence of a cluster of cells expressing low levels of

CD

93 when compared with all other lung endothelial cells but similar levels of

CLEC

14A (grey ellipse).

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