SIGLEC15

Official Full Name

sialic acid binding Ig like lectin 15

Organism

Homo sapiens

Gene ID

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

Cat.No.	Product Name	Price
CSC-DC014242	Panoply™ Human SIGLEC15 Knockdown Stable Cell Line	Inquiry
CSC-SC014242	Panoply™ Human SIGLEC15 Over-expressing Stable Cell Line	Inquiry
CSC-RO0466	Human SIGLEC15 Stable Cell Line - CHO-K1	Inquiry
CSC-RO0570	Human SIGLEC15 Stable Cell Line - HEK293T	Inquiry
CSC-RO0619	Human SIGLEC15 Stable Cell Line - MC38	Inquiry
CSC-RO0620	Human SIGLEC15 Stable Cell Line - CT26	Inquiry
CSC-RO0621	Human SIGLEC15 Stable Cell Line - THP-1	Inquiry
CSC-RO0933	Mouse Siglec15 Stable Cell Line - MC38	Inquiry
CSC-RO0936	Mouse SIGLEC15 Stable Cell Line - CT26	Inquiry
CSC-RH0081M	Humanized SIGLEC15 Murine Tumor Cell Line	Inquiry
CSC-RH0130M	Humanized SIGLEC15 Murine Tumor Cell Line	Inquiry

Cat.No.	Product Name	Price
AD14670Z	Human SIGLEC15 adenoviral particles	Inquiry
LV25391L	human SIGLEC15 (NM_213602) lentivirus particles	Inquiry

Cat.No.	Product Name	Price
SHH407452	shRNA set against Human SIGLEC15 (NM_213602.2)	Inquiry

Cat.No.	Product Name	Price
RP00323	Recombinant Human Siglec-15 (C-mFc)	Inquiry
RP00329	Biotinylated Human Siglec-15 (C-Fc-Avi)	Inquiry
RP00336	Recombinant Mouse Siglec-15 (C-6His)	Inquiry
RP00347	Recombinant Human Siglec-15 (C-Fc)	Inquiry
RP00355	Recombinant Human Siglec-15 (C-6His)	Inquiry
RP00390	Recombinant Cynomolgus Siglec-15 (C-Fc)	Inquiry
RP00392	Recombinant Cynomolgus Siglec-15 (C-6His)	Inquiry

Cat.No.	Product Name	Price
CDCB194924	Rabbit SIGLEC15 ORF clone (XM_008261253.1)	Inquiry
MiUTR4H-TG08073	SIGLEC15 miRNA 3'UTR clone	Inquiry
CDCB159505	Human SIGLEC15 ORF clone (NM_213602.2)	Inquiry
CDCH080210	Mouse Siglec15 ORF clone (NM_001101038.1)	Inquiry

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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