SEMA4D - semaphorin 4D |Elisa - Clia - Antibody - Protein

Background

SEMA4D, also known as CD100, is a member of the semaphorin family, a group of proteins primarily involved in axonal guidance during neural development. SEMA4D was initially identified for its role in the nervous system, where it facilitates signaling for axonal growth and directionality. It is now known to have significant functions beyond neural tissue, impacting immune system responses, vascular biology, and cancer. By interacting with various receptor families, SEMA4D modulates cell-cell communication, cell migration, angiogenesis, and immune activation.

In the immune system, SEMA4D is found on T cells, B cells, and dendritic cells, where it regulates immune responses by influencing cell adhesion, migration, and cytokine production. It has also become a molecule of interest in oncology, given its role in tumor progression, angiogenesis, and metastasis. SEMA4D is overexpressed in several cancer types, and its inhibition has shown promising results in reducing tumor growth and spread. Additionally, SEMA4D's involvement in blood vessel growth (angiogenesis) through its effects on endothelial cells and pericytes further highlights its importance in cancer biology and therapeutic potential.

Protein Structure

The SEMA4D protein consists of around 862 amino acids, resulting in a molecular weight of approximately 150 kDa. It is a type I transmembrane glycoprotein with a structure that aligns it with the semaphorin family.

Semaphorin (SEMA) Domain:

• The SEMA domain, located at the N-terminal, is the primary feature of SEMA4D and is shared by all members of the semaphorin family. This domain contains about 500 amino acids and is responsible for the protein's ability to bind its receptors, primarily Plexin-B1, Plexin-B2, and CD72. Structurally, the SEMA domain has a seven-bladed β-propeller configuration, which facilitates interactions with other cell surface receptors and ligands.

Immunoglobulin-like (Ig-like) Domain:

• Following the SEMA domain is a single Ig-like domain, which provides additional structural stability to the protein. This domain is necessary for proper receptor binding and plays a role in modulating the signaling pathways activated by SEMA4D.

Basic-rich and Transmembrane Domain:

• SEMA4D contains a basic-rich region, which aids in receptor interactions, especially with plexins on target cells. The transmembrane domain anchors SEMA4D to the cell membrane, allowing it to interact with other cells in its vicinity.

Cytoplasmic Tail:

• The cytoplasmic tail of SEMA4D is relatively short and does not have intrinsic enzymatic activity. Instead, it relies on the cytoplasmic domains of its receptors, especially the plexins, to transduce intracellular signals. This tail enables the recruitment of adaptor proteins that facilitate downstream signaling events.

Classification and Subtypes

SEMA4D belongs to the semaphorin family, a diverse group of proteins that are further divided into eight classes based on structure and origin. The classes include both secreted and membrane-bound semaphorins. SEMA4D is classified as a class 4 transmembrane semaphorin and specifically labeled as SEMA4D within this classification.

• Plexin-B1/B2: These receptors are part of the plexin family and are widely recognized as primary receptors for SEMA4D. When SEMA4D binds to these plexins, it initiates signaling pathways involved in cell migration, cytoskeletal rearrangement, and angiogenesis.
• CD72: In immune cells, SEMA4D can interact with CD72, primarily influencing immune responses and modulating T and B cell functions.

Function and Biological Significance

Axon Guidance:

• SEMA4D has a well-defined role in the nervous system, where it serves as an axonal guidance cue. By binding to plexins, particularly Plexin-B1, SEMA4D regulates axonal extension and directionality, which are crucial in establishing proper neural connections.

Immune Modulation:

• SEMA4D is expressed on T and B cells, where it acts as a costimulatory molecule in the immune response. Through interactions with CD72 on B cells and Plexin-B1/B2 on other immune cells, SEMA4D modulates cell migration, activation, and cytokine release. In T cells, SEMA4D enhances immune activation, whereas in B cells, it influences cell proliferation and differentiation.
• In dendritic cells, SEMA4D aids in maturation and migration to lymphoid organs, supporting antigen presentation and T cell priming.

Vascular and Tumor Angiogenesis:

• SEMA4D significantly influences angiogenesis, the formation of new blood vessels. By interacting with Plexin-B1 on endothelial cells, SEMA4D promotes angiogenic signaling, leading to new vessel formation. This function is critical in both normal tissue repair and tumor progression.
• In cancer, SEMA4D overexpression has been linked to enhanced tumor vascularization, providing the tumor with nutrients and oxygen that facilitate growth and metastasis.

Cancer Progression and Metastasis:

• SEMA4D is implicated in various cancers, where it supports tumor cell invasion and metastasis by promoting the breakdown of the extracellular matrix and enhancing cell motility. Its effects on angiogenesis further contribute to the metastatic potential of tumors, as increased vascularization allows tumor cells to disseminate more easily.
• Additionally, SEMA4D's interactions with Plexin-B1 on cancer cells activate pathways involved in cytoskeletal reorganization, facilitating invasion and spread.

Clinical Issues

Cancer:

• Diagnostic Marker: SEMA4D is overexpressed in several cancers, including breast, prostate, and pancreatic cancers, making it a potential biomarker for cancer progression.
• Therapeutic Target: Inhibitors of SEMA4D, such as monoclonal antibodies, are under investigation for their ability to reduce tumor growth and angiogenesis. By blocking SEMA4D, these therapies aim to limit tumor vascularization and the metastatic potential of cancer cells.
• Prognostic Indicator: Elevated levels of SEMA4D in tumors are often correlated with poor prognosis, as high SEMA4D expression is associated with increased vascularization and metastatic spread.

Immune-related Diseases:

• Given SEMA4D's role in immune cell activation and migration, it is implicated in autoimmune diseases and inflammatory conditions. Dysregulation of SEMA4D expression can lead to abnormal immune responses, contributing to conditions like rheumatoid arthritis.
• Therapeutic approaches targeting SEMA4D-CD72 interactions in immune cells are being explored for modulating immune responses in autoimmunity and chronic inflammation.

Neurological Disorders:

• As SEMA4D is crucial in axonal guidance and neural development, its dysregulation can contribute to neurological disorders. Abnormal SEMA4D signaling has been linked to neurodegenerative diseases, where altered axon pathfinding and cell signaling disrupt neural function. While research in this area is ongoing, SEMA4D modulation could provide insights into therapeutic strategies for neurological conditions.

Summary

SEMA4D is a multifunctional transmembrane protein involved in axonal guidance, immune regulation, angiogenesis, and tumor progression. Structurally, it comprises a characteristic SEMA domain, an immunoglobulin-like domain, a basic-rich region, and a transmembrane domain anchoring it to the cell membrane. SEMA4D primarily interacts with Plexin-B1 and CD72 receptors, which mediate its signaling effects in various tissues.

Functionally, SEMA4D has a crucial role in neural and immune cell communication, where it modulates axonal pathfinding, immune cell migration, and cytokine release. In cancer biology, SEMA4D promotes tumor angiogenesis and metastasis, making it a significant target in cancer therapy. Clinically, SEMA4D is under investigation as a biomarker and therapeutic target in oncology, with potential applications in immune modulation for autoimmune and inflammatory diseases. As research progresses, SEMA4D's dual roles in promoting both tissue health and disease underscore its complexity and potential as a therapeutic target.