SIGLEC15

Official Full Name

sialic acid binding Ig like lectin 15

Organism

Homo sapiens

GeneID

284266

Background

Predicted to be involved in regulation of actin cytoskeleton organization; regulation of bone resorption; and regulation of osteoclast development. Predicted to be located in membrane. Predicted to be part of protein-containing complex. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

CD33L3; HsT1361; SIGLEC-15;

Bio Chemical Class

Immunoglobulin

Protein Sequence

MEKSIWLLACLAWVLPTGSFVRTKIDTTENLLNTEVHSSPAQRWSMQVPPEVSAEAGDAAVLPCTFTHPHRHYDGPLTAIWRAGEPYAGPQVFRCAAARGSELCQTALSLHGRFRLLGNPRRNDLSLRVERLALADDRRYFCRVEFAGDVHDRYESRHGVRLHVTAAPRIVNISVLPSPAHAFRALCTAEGEPPPALAWSGPALGNSLAAVRSPREGHGHLVTAELPALTHDGRYTCTAANSLGRSEASVYLFRFHGASGASTVALLLGALGFKALLLLGVLAARAARRRPEHLDTPDTPPRSQAQESNYENLSQMNPRSPPATMCSP

Open

Disease

Non-small-cell lung cancer

Approved Drug

Clinical Trial Drug

1 +

Discontinued Drug

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Detailed Information

Siglec-15, also known as CD33 antigen-like 3, is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family. The SIGLEC15 gene is located on human chromosome 18q22.3 and encodes a type I transmembrane protein composed of an N-terminal V-set immunoglobulin domain responsible for sialic acid recognition, a C2-set immunoglobulin domain, a transmembrane region, and a short intracellular domain. The intracellular portion contains a key immunoreceptor tyrosine-based inhibitory motif (ITIM) and a tyrosine-based switch motif (ITSM), which mediate inhibitory signaling. Evolutionary analysis shows that SIGLEC15 is highly conserved, with SIGLEC8 as a paralog sharing partial functional similarity. The protein specifically binds sialylated glycoproteins in a calcium-dependent manner, and although it exhibits relatively low affinity, multivalent clustering on the cell surface enhances its effective binding.

Figure 1. Clinical application of Siglec family members. (Sun J, et al., 2021)

Expression and Distribution

Under normal physiological conditions, SIGLEC15 is expressed at low levels in osteoclast precursors, macrophage subsets, and immature dendritic cells. Expression is upregulated by transcription factors such as PU.1 and MITF during osteoclast differentiation. In pathological contexts, including the tumor microenvironment, SIGLEC15 is aberrantly overexpressed on tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and some epithelial tumor cells, suggesting a role in tumor immune evasion.

Innate Immune Modulation

SIGLEC15 regulates osteoclast differentiation and bone homeostasis. SIGLEC15-deficient mice show increased bone density due to reduced osteoclast formation. Mechanistically, SIGLEC15 recruits SHP-1 and SHP-2 phosphatases via its ITIM motif, attenuating RANKL-induced NF-κB and NFATc1 activation to negatively regulate osteoclast maturation. It also participates in osteoblast-osteoclast communication to maintain bone remodeling balance. Beyond bone metabolism, SIGLEC15 modulates macrophage function by recognizing sialylated pathogen-associated molecular patterns (PAMPs) and suppressing TLR signaling, limiting excessive inflammation in infection models.

Tumor Immune Evasion

As an emerging immune checkpoint molecule, SIGLEC15 mediates immunosuppression in the tumor microenvironment. It binds sialylated glycan ligands on T cells, triggering phosphorylation of its ITIM domain and recruiting SHP-1/SHP-2 phosphatases. This dephosphorylates key T cell receptor (TCR) signaling molecules such as CD3ζ and ZAP70, inhibiting T cell activation and proliferation. SIGLEC15 expression is mutually exclusive with PD-L1, indicating a distinct pathway for immunosuppression. Single-cell transcriptomics show that high SIGLEC15 expression correlates with CD8+ T cell exhaustion markers (TIM-3, LAG-3), reduced effector molecule expression (IFN-γ, granzyme B), and enhanced regulatory T cell differentiation and MDSC expansion. In vitro and in vivo studies demonstrate that blocking SIGLEC15 enhances T cell cytotoxicity and reduces tumor growth in a T cell-dependent manner.

Regulation of Tumor Cell Proliferation and Invasion

SIGLEC15 also directly influences tumor cell malignant behaviors. In laryngeal squamous cell carcinoma, SIGLEC15 activates the EGFR/PI3K/AKT pathway, promoting proliferation and survival. Knockdown of SIGLEC15 leads to cell cycle arrest in G1/S, associated with upregulation of CDK inhibitors p21 and p27. It enhances cell migration and invasion via the RhoA/ROCK pathway and is positively correlated with epithelial-mesenchymal transition markers such as N-cadherin and vimentin. SIGLEC15 contributes to tumor metabolic reprogramming by activating PI3K/AKT/mTOR signaling and upregulating glycolytic enzymes (HK2, LDHA), supporting aerobic glycolysis and producing lactate that suppresses T cell function, creating a pro-tumor feedback loop.

Reference

Sun J, Lu Q, Sanmamed MF, et al. Siglec-15 as an Emerging Target for Next-generation Cancer Immunotherapy. Clin Cancer Res. 2021 Feb 1;27(3):680-688.

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