Semaphorin 6B is a member of the class 6 subfamily of semaphorins, a large, highly conserved family of signaling molecules that affect multiple processes including axon guidance, cell migration, synaptogenesis, and dendritic spine formation (1). The class 6 semaphorins are type I transmembrane glycoproteins that contain the characteristic extracellular beta propeller-structured N-terminal semaphorin (sema) domain and also an extracellular plexin-semaphorin-integrin (PSI) domain (2, 3). Additionally, the cytoplasmic domain of Semaphorin 6B contains a proline-rich sequence that has been shown to interact with the SH3 domain of the Src signaling protein (4). Human Semaphorin 6B has a molecular weight of approximately 120 kDa and shares 95% and 94% amino acid (aa) sequence identity with the mouse and rat orthologs, respectively. Full-length Semaphorin 6B is thought to form disulfide-linked homodimers (4). Alternative exon splicing creates a 492 aa isoform that may be secreted (Semaphorin 6B.1) and a 657 aa isoform with a shortened cytoplasmic tail (Semaphorin 6B.2) (5). Semaphorin 6B is highly expressed in heart and brain and is observed in most other tissues at lower levels (5). Semaphorin 6B has also been shown to be highly expressed in human gastric, breast, and glioblastoma cancer cells and is thought to be involved in tumor differentiation and metastasis (5-7). Interestingly, retinoic acid, which slows cancer cell growth, has been shown to down-regulate Semaphorin 6B expression (5, 6). It is hypothesized the retinoid X receptors (RXRs) form heterodimers with peroxisome proliferator-activated receptors (PPARs), which then bind to a putative peroxisome proliferator-responsive element (PPRE) in the SEMA6B promoter region (6, 8, 9). Semaphorin 6B has also been shown to mediate repulsion of mouse sympathetic ganglion axons and hippocampal mossy fibers via binding to the transmembrane protein Plexin A4 (10, 11).