The semaphorins

Abstract

Semaphorins are secreted, transmembrane, and GPI-linked proteins, defined by cysteine-rich semaphorin protein domains, that have important roles in a variety of tissues. Humans have 20 semaphorins, Drosophila has five, and two are known from DNA viruses; semaphorins are also found in nematodes and crustaceans but not in non-animals. They are grouped into eight classes on the basis of phylogenetic tree analyses and the presence of additional protein motifs. The expression of semaphorins has been described most fully in the nervous system, but they are also present in most, or perhaps all, other tissues. Functionally, semaphorins were initially characterized for their importance in the development of the nervous system and in axonal guidance. More recently, they have been found to be important for the formation and functioning of the cardiovascular, endocrine, gastrointestinal, hepatic, immune, musculoskeletal, renal, reproductive, and respiratory systems. A common theme in the mechanisms of semaphorin function is that they alter the cytoskeleton and the organization of actin filaments and the microtubule network. These effects occur primarily through binding of semaphorins to their receptors, although transmembrane semaphorins also serve as receptors themselves. The best characterized receptors for mediating semaphorin signaling are members of the neuropilin and plexin families of transmembrane proteins. Plexins, in particular, are thought to control many of the functional effects of semaphorins; the molecular mechanisms of semaphorin signaling are still poorly understood, however. Given the importance of semaphorins in a wide range of functions, including neural connectivity, angiogenesis, immunoregulation, and cancer, much remains to be learned about these proteins and their roles in pathology and human disease.

Figure 1

A phylogenetic tree of semaphorin sequences, showing groupings of related semaphorin genes and their organization into different classes. D, Drosophila; M, mouse; V, viral; Z, sequence identified only in zebrafish and not in mammals. A Sema5D has also been described, but our analysis indicates that it is a splice variant of Sema5B. Protein sequences were aligned using ClustalW in Vector NTI software and the tree was generated using the neighbor-joining method, ignoring positions with gaps.

Figure 2

Primary structures of members of the semaphorin family. All proteins are shown with their amino termini to the top. Class 1 semaphorins are invertebrate transmembrane proteins and are structurally very similar to the class 6 semaphorins of vertebrates. Class 2 semaphorins (also from invertebrates) are secreted; they are structurally similar to vertebrate class 3 semaphorins, which have a stretch of highly basic amino acids in their carboxy-terminal region. Class 4, 6, and 7 semaphorins have been identified only in vertebrates. Class 4-6 semaphorins are transmembrane proteins. Class 5 semaphorins are present in both vertebrates (Sema5A, Sema5B) and invertebrates (Sema5c) and contain seven canonical type 1 thrombospondin repeats (TSRs). Class 6 semaphorins contain variable, alternatively spliced cytoplasmic portions. The lone class 7 sema (Sema7A) contains a membrane-associated GPI moiety at its carboxy terminus. Class V semaphorins are highly similar to class 7 semaphorins and are found in DNA viruses, including vaccinia (a close relative to the cowpox virus), human smallpox (variola virus), fowlpox, mousepox (ectromelia virus), and alcelaphine herpesvirus type 1 virus (AHV). Some class V semaphorins (the SemaVA proteins) do not contain an Ig domain, whereas others do (SemaVB proteins). Sema, semaphorin; PSI, plexin-semaphorin-integrin; Ig, immunoglobulin-like; GPI, glycosylphosphatidylinositol.

Figure 3

Semaphorin receptors. Members of the plexin protein family are organized into four classes (A, B, C, and D); plexins are known to bind to semaphorins from all classes except class 2, whose receptors are unknown. Class 3 semaphorins bind both members of the neuropilin protein family. Sema4A binds Tim-2, a member of the T cell, immunoglobulin and mucin (Tim) domain protein family expressed on activated T cells [27]. Sema 4D binds CD72, a member of the C-type lectin family, and uses it for its effects in lymphoid tissues [27]. Sema, semaphorin; PSI, plexin-semaphorin-integrin; IPT, immunoglobulin-like fold shared by plexins and transcription factors; GAP, GTPase-activating protein; MAM, Meprin, A5, Mu; PMR, polymorphic region; ITIM, immunoreceptor tyrosine-based inhibitory motif; IgV, immunoglobulin variable region.