Receptor Functions of Semaphorin 4D

Semaphorin 4D (Sema4D) is a multifunctional protein widely expressed in an organism that plays an important role in the control of many physiological and pathological processes, including immunoregulation, neurogenesis, angiogenesis, and tumor progression. It was first described almost 30 years ago and has been actively studied since then. However, with rare exceptions, all studies of the Sema4D activity proceed from the assumption that semaphorin is a ligand that acts through specific receptors (CD72 and plexins) and that the main targets of Sema4D in different tissues are cells that carry these receptors on the membrane. This review analyzes the data indicating the presence of an alternative mechanism for the regulatory activity of Sema4D that involves the functioning of membrane semaphorin as a receptor ensuring the outside-in signaling. Cell signaling pathways mediated by the membrane Sema4D and their contribution to the Sema4D-dependent regulation of cell functions are discussed.