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CD144, also known as vascular endothelial cadherin (VE-cadherin) or cadherin-5 (CDH5), is the endothelial-specific adhesion molecule that forms the structural and signaling core of the adherens junction. Unlike the broadly expressed PECAM1, CD144 is found almost exclusively on endothelial cells, where it tethers adjacent cells and couples them to the actin cytoskeleton. Over the past decade, live imaging, knock-in mouse models with site-specific phosphorylation or ubiquitination mutants, and structural biology have transformed CD144 from a passive "glue" into a dynamic, phosphorylation-regulated gatekeeper of vascular integrity. This review examines its structure, its control of barrier function and permeability, its roles in angiogenesis and leukocyte trafficking, its involvement in disease, and its promise as a therapeutic target.
CD144 is a classical type II cadherin whose extracellular region contains five ectodomains (EC1-EC5) that mediate calcium-dependent, homophilic adhesion between neighboring endothelial cells. The membrane-proximal EC1 domain carries the adhesive interface, while the intracellular tail binds p120-catenin, β-catenin, and plakoglobin, linking the junction to the actin cytoskeleton through α-catenin. This cadherin-catenin complex is the molecular scaffold of the adherens junction and the foundation of endothelial monolayer integrity. CD144 does not operate alone: it forms important complexes with transmembrane partners including PECAM1, VEGFR2, Tie2, and vascular endothelial protein tyrosine phosphatase (VE-PTP). Through these partnerships, CD144 serves as a signaling node that maintains vascular integrity rather than merely a static adhesive clamp. Importantly, the CD144-catenin complex is also tension-sensitive: the homophilic bond strengthens under applied force, allowing the junction to resist the shear stresses of blood flow while remaining pliable enough to permit cell rearrangement during sprouting. This catch-bond-like behavior means the same receptor can act as both a rigid seal under flow and a dynamic hinge during remodeling — a duality that has reshaped how adhesion is modeled at the molecular level.
Figure 1. Multiple Functions of Adherens Junctions in Endothelial Cells.
(Source: Giannotta M, et al. 2013)
The primary duty of CD144 is to maintain vascular barrier integrity by tethering adjacent endothelial cells and setting the baseline resistance of the vessel wall to fluid and solute flux. Permeability-increasing stimuli — VEGF, histamine, thrombin — trigger CD144 phosphorylation, endocytosis, and weakened homophilic binding, opening the junction. A growing literature details negative regulators: soluble CD144 ectodomain shed during systemic inflammation disrupts CD144–VE-PTP interactions and activates RhoA, driving barrier breakdown in sepsis; ubiquitination of CD144 at lysine residues K626 and K633 promotes its turnover and increases vascular leak in vivo; and cleavage by ADAM metalloproteases loosens junctions in aneurysm and inflammatory arthritis. Counter-regulatory mechanisms exist — CD93 limits CD144 phosphorylation and turnover to preserve barrier, and sphingosine-1-phosphate receptor 1 restrains CD144 cleavage. Together these findings establish CD144 as a tunable gate rather than a fixed seal. Notably, this regulation is region-specific: venous endothelium, which experiences lower shear, shows higher basal CD144 phosphorylation and is more permissive than arterial endothelium, an asymmetry that helps explain why inflammatory leak and leukocyte entry favor veins over arteries in many tissues.
The past two years have pinpointed exactly which post-translational modifications open the junction. A 2024 study showed that histamine and thrombin stimulate ubiquitination of CD144 at lysines K626 and K633, and that replacing these residues with arginine blocks stimulus-induced endocytosis and sharply reduces vascular permeability in the skin and lung of knock-in mice. A 2025 follow-up dissected serine and tyrosine phosphorylation sites: phosphorylation of S665 and the previously known Y685 were strongly induced by inflammatory mediators and required for histamine- or VEGF-driven leak, whereas Y658 proved irrelevant in vivo. Mechanistically, Y685 phosphorylation licenses bradykinin-induced endocytosis downstream of which K626/K633 ubiquitination targets CD144 for lysosomal degradation. These site-specific insights convert a vague "junction opens" into a precise molecular choreography that can be targeted.
Figure 2. Mechanisms for the in vivo control of leukocyte diapedesis and vascular permeability by phosphorylated VE-cadherin.
(Source: Sidibé A, et al. 2014)
Beyond quiescent vessels, CD144 is indispensable for building new ones. During sprouting angiogenesis, endothelial cells reorganize into tip and stalk cells, a transition that demands controlled remodeling of adherens junctions. CD144 phosphorylation and transient endocytosis permit the cell shape changes and motility required for sprouting, while its continued presence anchors the nascent lumen. VEGF-A stimulation shifts CD144 from a quiescent, phosphatase-maintained state into a Src-phosphorylated state that, through VEGFR2, drives PI3K/AKT survival, ERK/MAPK proliferation, and migration. Dysregulated CD144 signaling contributes to pathological angiogenesis in tumors and ocular neovascularization, making it a double-edged target: too little impairs wound healing and tissue perfusion, too much fuels aberrant vessel growth. A 2023 review highlighted CD144's role in tumor-associated vasculogenic mimicry, where aggressive cancer cells themselves express endothelial markers including CD144 to build perfusion channels independent of normal endothelium. The lumen-forming step is especially CD144-dependent: as tip cells extend filopodia and stalk cells elongate, transient CD144 internalization at the rear of migrating cells, coupled with stable CD144 at the nascent lumen, preserves a patent vascular channel. Disruption of this choreography produces shunted or non-productive sprouts, highlighting CD144 as a quality-control factor in vessel patterning rather than a passive bystander.
CD144 also governs how leukocytes cross the endothelial barrier. Paracellular migration — the dominant route in many tissues — requires transient opening of CD144-mediated adherens junctions, whereas transcellular routes bypass them. The same phosphorylation and endocytosis machinery that controls permeability also licenses diapedesis: in a 2024 stroke model, a CD144 mutation that inhibits leukocyte migration reduced infarct volumes and improved motor outcomes, demonstrating that junctional CD144 state directly shapes neuroinflammatory injury. CD144 in arachnoid and pia mater cells has even been proposed as a landmark for in vivo imaging of CNS immune surveillance, underscoring how consistently this molecule marks the endothelial border across vascular beds.
The clinical footprint of CD144 is broad. In systemic inflammation and sepsis, shed soluble CD144 correlates with organ dysfunction and the need for resuscitation, positioning it as both a biomarker and a mechanistic driver of vascular collapse. In the brain, CD144 mutation-based inhibition of leukocyte entry protects against ischemic injury. Aneurysm and dissection are associated with elevated CD144 cleavage, and inflammatory arthritis is attenuated when CD144 cleavage is restrained. In the eye, CD144 sits downstream of VEGF in diabetic retinopathy, where its expression and phosphorylation status track retinal vascular leakage and neovascularization, making it a candidate target for vision-threatening disease. In the skin and lung, the ubiquitination-dependent permeability pathway places CD144 squarely at the center of inflammatory edema. These links reframe endothelial junctions as active participants in, not mere victims of, disease.
Manipulating CD144 holds promise across indications. Stabilizing it — via agents that preserve its interaction with VE-PTP or inhibit its cleavage — could protect the barrier in sepsis, ischemia-reperfusion, and inflammatory injury. Enhancing CD93 or sphingosine-1-phosphate signaling limits CD144 turnover and may have analogous benefit. Conversely, transiently loosening CD144 could improve drug or oxygen delivery to tumors. The challenge is specificity: junctions are ubiquitous, so interventions must be tissue-targeted or context-specific. Encouragingly, the atomic dissection of CD144 regulatory modifications provides concrete molecular handles — particular phosphorylation and ubiquitination sites — that can be engaged without broadly disabling adhesion.
References
| Target | Cat. No. | Product Name | Size | Species | Application | Detection Sample | |
| CDH5 | DEIA2928 | Human VE-Cadherin ELISA Kit | 96T | Human | Quantitative | Cell culture supernatants, serum, plasma | Inquiry |
| DEIA-XYA2013 | VE-Cadherin ELISA Kit | 96T | Qualitative | Cultured cells | Inquiry |
| Target | Cat. No. | Product Name | Host | Isotype | Application | |
| CDH5 | CDABT-ZL399 | CleanFc 6 4 Rabbit Anti-Human VE-cadherin/CD144 Monoclonal antibody, clone 351866C3 [APC] | Rabbit | IgG | FC | Inquiry |
| CDABT-ZL400 | CleanFc 6 4 Rabbit Anti-Human VE-cadherin/CD144 Monoclonal antibody, clone 351866C3 [Biotin] | Rabbit | IgG | FC | Inquiry | |
| CDABT-ZL401 | CleanFc 6 4 Rabbit Anti-Human VE-cadherin/CD144 Monoclonal antibody, clone 351866C3 [PE] | Rabbit | IgG | FC | Inquiry | |
| CDABT-ZL620 | CleanFc 6 4 Rabbit Anti-Mouse VE-cadherin/CD144 Monoclonal antibody, clone 352064E5 [Biotin] | Rabbit | IgG | FC, ELISA | Inquiry |
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