SEMA4D

Official Full Name

semaphorin 4D

Organism

Homo sapiens

GeneID

10507

Background

Enables identical protein binding activity; semaphorin receptor binding activity; and transmembrane signaling receptor activity. Involved in several processes, including ossification involved in bone maturation; positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; and regulation of neuron projection development. Located in plasma membrane. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

A8; GR3; BB18; CD100; COLL4; SEMAJ; coll-4; C9orf164; M-sema-G;

Protein Sequence

MRMCTPIRGLLMALAVMFGTAMAFAPIPRITWEHREVHLVQFHEPDIYNYSALLLSEDKDTLYIGAREAVFAVNALNISEKQHEVYWKVSEDKKAKCAEKGKSKQTECLNYIRVLQPLSATSLYVCGTNAFQPACDHLNLTSFKFLGKNEDGKGRCPFDPAHSYTSVMVDGELYSGTSYNFLGSEPIISRNSSHSPLRTEYAIPWLNEPSFVFADVIRKSPDSPDGEDDRVYFFFTEVSVEYEFVFRVLIPRIARVCKGDQGGLRTLQKKWTSFLKARLICSRPDSGLVFNVLRDVFVLRSPGLKVPVFYALFTPQLNNVGLSAVCAYNLSTAEEVFSHGKYMQSTTVEQSHTKWVRYNGPVPKPRPGACIDSEARAANYTSSLNLPDKTLQFVKDHPLMDDSVTPIDNRPRLIKKDVNYTQIVVDRTQALDGTVYDVMFVSTDRGALHKAISLEHAVHIIEETQLFQDFEPVQTLLLSSKKGNRFVYAGSNSGVVQAPLAFCGKHGTCEDCVLARDPYCAWSPPTATCVALHQTESPSRGLIQEMSGDASVCPDKSKGSYRQHFFKHGGTAELKCSQKSNLARVFWKFQNGVLKAESPKYGLMGRKNLLIFNLSEGDSGVYQCLSEERVKNKTVFQVVAKHVLEVKVVPKPVVAPTLSVVQTEGSRIATKVLVASTQGSSPPTPAVQATSSGAITLPPKPAPTGTSCEPKIVINTVPQLHSEKTMYLKSSDNRLLMSLFLFFFVLFLCLFFYNCYKGYLPRQCLKFRSALLIGKKKPKSDFCDREQSLKETLVEPGSFSQQNGEHPKPALDTGYETEQDTITSKVPTDREDSQRIDDLSARDKPFDVKCELKFADSDADGD

Open

Disease

Choreiform disorder, Lung cancer, Metastatic lymph node neoplasm, Multiple sclerosis

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

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Detailed Information

Semaphorin 4D (SEMA4D), also known as CD100, belongs to the class IV semaphorin subfamily and functions as a cell surface receptor for PLXNB1 and PLXNB2. It plays important roles in intercellular signaling and is a transmembrane glycoprotein involved in neurogenesis, immune regulation, and angiogenesis. CD100 is broadly expressed across tissues and cell types. It is highly expressed in oligodendrocytes, NK cells, T cells, and monocytes, with lower expression in granulocytes, macrophages, Hofbauer cells, Kupffer cells, and dendritic cells.

Structure and Receptors

CD100 is a 150 kDa transmembrane glycoprotein consisting of 862 amino acids. Its structure includes three major regions: a cytoplasmic domain containing serine phosphorylation sites, a transmembrane segment, and a large extracellular domain with conserved motifs. The extracellular domain contains a hallmark SEMA domain of about 500 amino acids responsible for receptor binding, an immunoglobulin-like domain, and a conserved PSI domain. Proteolytic cleavage of the extracellular region by enzymes such as ADAM10 and MMP2/9 generates a soluble 120 kDa form (sCD100), which functions as a ligand in immune regulation. CD100 interacts with two classes of receptors: high-affinity Plexin family members (Plexin-B1 and Plexin-B2) and the low-affinity receptor CD72.

Figure 1. The structure of CD100. (Zhao M, et al., 2025)

Functions in Immune Cells

CD100 exerts diverse effects on immune cells. It enhances T cell activation through both direct mechanisms and dendritic cell–mediated regulation. Interaction with CD72 promotes dendritic cell activation and maturation, while binding to Plexin-B1 limits dendritic cell migration. In B cells, CD100–CD72 interaction prevents SHP-1 recruitment to ITIM motifs, supporting proliferation and antibody production. On NK cells, membrane-bound CD100 binding to CD72 or Plexin-B1/B2 enhances adhesion, degranulation, and IFN-γ secretion, while interaction with Plexin-B2 inhibits Rac1-dependent ROS generation and NET formation. In macrophages, CD100–CD72 interaction promotes parasite phagocytosis, whereas CD100–Plexin-B2 interaction downregulates CD36 expression and reduces oxLDL uptake, also favoring M2-like polarization.

Signaling in Cancer

Membrane-bound SEMA4D can be cleaved by MT1-MMP to produce a soluble form that binds Plexin-B1 receptors on tumor cells, endothelial cells, and immune cells in the tumor microenvironment. This binding leads to transactivation of tyrosine kinase receptors such as Met and ErbB2, activation of the small GTPase RhoA, and subsequent phosphorylation of MAPK and Akt signaling cascades. SEMA4D-mediated activation of RhoA is associated with increased invasiveness and metastatic potential, highlighting its role in cancer progression.

Figure 2. Semaphorin signaling in cancer cells. (Mastrantonio R, et al., 2021)

Therapeutic Targeting

Pepinemab (VX15/2503) is a monoclonal antibody targeting SEMA4D that has been tested in clinical trials for recurrent or metastatic head and neck squamous cell carcinoma, Huntington’s disease, and Alzheimer’s disease. Phase II studies in Huntington’s disease and non-small cell lung cancer have been completed, with future phase III trials in Huntington’s disease being planned. Beyond these indications, Pepinemab also holds potential for treating other cancers and neurodegenerative conditions such as multiple sclerosis, amyotrophic lateral sclerosis, and Rett syndrome.

Reference

Zhao M, Chen L, Chen Y, et al. Research Advances in the Immunomodulatory Functions of CD100/SEMA4D and Their Roles in Viral Infectious Diseases. Int J Mol Sci. 2025 May 2;26(9):4341.
Mastrantonio R, You H, Tamagnone L. Semaphorins as emerging clinical biomarkers and therapeutic targets in cancer. Theranostics. 2021 Jan 15;11(7):3262-3277.

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