Understanding SEZ6: Structure, Functions, and Therapeutic Potential

Seizure-related 6 homolog (SEZ6) is a protein encoded by the SEZ6 gene in humans.

Initially identified due to its upregulation in neurons following seizure activity, SEZ6 has since been recognized for its significant roles in neural development and function.

Structural Characteristics of SEZ6

SEZ6 is a type I transmembrane protein characterized by several distinct domains:

• Sushi Domains: Also known as short consensus repeat (SCR) domains, SEZ6 contains five of these cysteine-rich motifs. Sushi domains are implicated in various recognition processes, including binding of complement factors to C3b and C4b fragments.

   

• CUB Domains: SEZ6 possesses two to three CUB domains, structural motifs found in proteins involved in developmental processes.

   

• Transmembrane Domain: Anchors SEZ6 to the cell membrane, positioning it to participate in cell signaling.

Alternative splicing of SEZ6 mRNA results in different isoforms:

• Membrane-bound Isoforms: Contain a single transmembrane domain.

• Secreted Isoform (sSEZ6): Lacks the transmembrane domain and is released extracellularly.

   

Physiological Roles of SEZ6

SEZ6 is predominantly expressed in the central nervous system and is integral to several neural processes:

• Dendritic Development: SEZ6 plays a role in the formation of neuronal dendrites, maintaining a balance between dendrite elongation and branching.

   

• Synaptic Connectivity: SEZ6 is involved in the development of appropriate excitatory synaptic connections, essential for effective neuronal communication.

   

• Neuronal Signaling: By facilitating cell-cell recognition and membrane signaling, SEZ6 contributes to the overall functionality of neural networks.

Clinical Implications of SEZ6

Mutations or dysregulation of SEZ6 have been associated with various neurological conditions:

• Febrile Seizures: Mutations in SEZ6 have been linked to febrile seizures, suggesting its role in neuronal excitability.

   

• Epilepsy: Given its association with seizure activity, SEZ6 may be implicated in certain forms of epilepsy.

  
  

   

SEZ6 in Oncology: A Novel Therapeutic Target

Beyond its neurological functions, SEZ6 has emerged as a potential target in cancer therapy:

• Overexpression in Tumors: SEZ6 is overexpressed in various tumor types, including small cell lung cancer (SCLC), neuroendocrine carcinomas (NECs), and central nervous system (CNS) tumors.

   

• Angiogenesis in Gliomas: In glioma stem-like cells (GSCs), SEZ6 has been shown to induce angiogenesis by activating the TGFβ pathway in endothelial cells, leading to increased IL8 production.

   

Therapeutic Strategies Targeting SEZ6

Given its overexpression in certain cancers, SEZ6 has been explored as a therapeutic target:

• Antibody-Drug Conjugates (ADCs): ABBV-706 is an ADC comprising an anti-SEZ6 antibody linked to a topoisomerase 1 inhibitor. A Phase I study is evaluating its safety and efficacy in patients with advanced solid tumors.

   

• BACE1 Inhibition: BACE1 cleaves SEZ6, releasing its extracellular domain. Inhibiting BACE1 prevents SEZ6 shedding, reducing its pro-angiogenic effects in gliomas.

   

Conclusion

SEZ6 is a multifaceted protein with pivotal roles in neural development and function. Its emerging significance in oncology highlights its potential as a therapeutic target. Ongoing research aims to elucidate SEZ6's functions further and develop targeted therapies to improve outcomes for patients with SEZ6-related pathologies.