Protein family review

This in an extract of a protein family review which first appeared in GenomeBiology, and is reproduced by permission of the publisher, BioMedCentral Ltd.

Authors:

Umar Yazdani and Jonathan R Terman

Center for Basic Neuroscience, Department of Pharmacology, NA4.301/5323 Harry Hines Blvd, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA

Correspondence:

Jonathan R Terman.

Email:

jonathan.terman@utsouthwestern.edu

Read the full article

Subscribers to GenomeBiology may view the full version of this review article online at http://genomebiology.com/2006/7/3/211

Published:

30 March 2006

The Semaphorins

Summary

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.

Frontiers

Despite considerable progress in our characterization of members of the semaphorin family, much remains to be learned about their functions and molecular mechanisms of action. Several semaphorins have yet to be functionally characterized, and many have undergone only a cursory examination. A number of questions remain, including the purpose of having so many related semaphorins and the underlying logic to their complex expression patterns and physiological roles. The degree of interaction among semaphorins is also poorly understood. Do they regulate each other's signaling cascades? Do they physically associate? What special attributes and abilities do the secreted, transmembrane, and GPI-linked forms of semaphorins functionally provide?

Understanding the signaling cascades that underlie the different functional effects of semaphorins will provide insights into these important proteins. Are there differences in the signaling cascades activated by the different semaphorins? How much do their signaling cascades vary in order to mediate their different cellular effects? How do semaphorins exert their dramatic effects on the cytoskeleton?

A more detailed understanding of the role of semaphorins in the normal functioning adult is important. In the nervous system, the role of semaphorins in forming neural connections is well established, but the role of semaphorins in neural connectivity as it pertains to thought, emotion, memory, and behavior is unknown. The role of semaphorins in human disease and pathology is also poorly understood. Mutations in semaphorins are associated with patients with cancer [28], retinal degeneration [51], decreased bone mineral density [52], rheumatoid arthritis [53], and CHARGE syndrome (a disorder characterized by cranial nerve dysfunction, cardiac anomalies, and growth retardation) [54]. Further characterization of the semaphorins and a better understanding of their signaling mechanisms will undoubtedly uncover additional roles for semaphorins and semaphorin signaling in human disease.

Given the role of semaphorins in a wide range of tissues and functions including neurobiology, vasculobiology, cancer biology, and immunobiology, further characterizing the semaphorins and their signaling cascades will reveal fundamental mechanisms of how these systems work and strategies for preventing and treating pathologies associated with them.

A phylogenetic tree of semaphorin sequences, showing groupings of related semaphorin genes and their organization into different classes

Primary structures of members of the semaphorin family