Semaphorin Signals in Cell Adhesion and Cell Migration: Functional Role and Molecular Mechanisms

Abstract

C ell migration is pivotal in embryo development and in the adult. During development, a wide range of progenitor cells travel over long distances before undergoing terminal differentiation. Moreover, the morphogenesis of epithelial tissues and of the cardio-vascular system involves remodelling compact cell layers and the sprouting of new tubular branches. In the adult, cell migration is essential for the leucocytes involved in immune response. Furthermore, invasive and metastatic cancer cells have the distinctive ability to overcome normal tissue boundaries, travel in and out the blood vessels, and settle down in heterologous tissues. Cell migration normally follows strict guidance cues, either attractive, or inhibitory and repulsive. Semaphorins are a wide family of signals guiding cell migration during development and in the adult. Recent findings have established that semaphorin receptors, the plexins, govern cell migration by regulating integrin-based cell substrate adhesion and actin cytoskeleton dynamics, via specific monomeric GTPases. Plexins furthermore recruit tyrosine kinases in receptor complexes, which allows switching between multiple signalling pathways and functional outcomes. In this article, we will review the functional role of semaphorins in cell migration and the implicated molecular mechanisms controlling cell adhesion.

Measles virus modulates dendritic cell/T‐cell communication at the level of plexinA1/neuropilin‐1 recruitment and activity

“…ligands determine whether they functionally support (by selfinteraction) or rather contribute to termination of (by SEMA3A interaction) the IS [22,23,44]. The importance of the ligandbinding NP-1 in the IS has been established in murine and human systems [32,45], and we now confirmed that, similar to the murine system, plexA1 is an important component of IS function (Fig.…”

“…The inability of MVexposed T cells to organize a correct synapse architecture has previously been described by us and the established interference of MV signalling with actin cytoskeletal dynamics expectedly accounts for aberrant sorting of receptors probably also including plexA1/NP-1 to this structure [18,47]. This could, however, not directly be confirmed in conjugates between MV-DC and T cells because the majority of these is highly unstable [10].In axon guidance, NP-1/SEMA3A signalling modified the growth cone cytoskeleton by causing retraction of filopodia and lamellopodia and localized rearrangement of the actin cytoskeleton [22]. Though it has not been directly addressed, interference with cytoskeletal dynamics might also account for the NP-1/SEMA3A-mediated loss of human thymocyte adhesion to thymic epithelial cells or their ECM-driven migration [35].…”

“…SEMA receptor signalling targets small GTPases and thereby actin dynamics and integrin activation, and adhesion [22,27,28]. Thus, plexinA1 (plexA1) and NP-1 were implicated in DC migration through endothelial layers and lymphatic entry [29], yet also in T-cell activation by murine or human DC [30][31][32], though neither their co-segregation at the IS nor their ligands there clearly identified.…”

“…Most membrane-resident SEMAs use members of the plexin family for binding and signalling, while most SEMA3 molecules require neuropilins (NP-1 or -2) as obligate binding receptors for initiating cellular responses through plexins. In addition to using these receptors, certain SEMAs (SEMA7A and SEMA4A and 4D) also signal to their immune effector cells by interaction with integrins, CD72, or TIM-2 [23,26].SEMA receptor signalling targets small GTPases and thereby actin dynamics and integrin activation, and adhesion [22,27,28]. Thus, plexinA1 (plexA1) and NP-1 were implicated in DC migration through endothelial layers and lymphatic entry [29], yet also in T-cell activation by murine or human DC [30][31][32], though neither their co-segregation at the IS nor their ligands there clearly identified.…”

“…It is an area of highly active cytoskeletal rearrangement, which essentially controls centripetal movement of TCR microclusters, but also receptor segregation including that of integrins, which regulate both TCR microcluster confinement and stability of the DC/T-cell conjugate (for a recent review [19]). Initially described as guidance factors regulating axonal pathfinding during neuronal development, the general ability of semaphorins (SEMAs) to act as adhesion/repulsion cues has meanwhile highlighted the importance of these molecules in diverse physiological functions also including vascular growth, cell migration, and immune cell regulation [20][21][22][23]. SEMAs share a common ''SEMA'' domain and are divided into eight subclasses, and those expressed in vertebrates are membrane associated (class IV-VII) or secreted (class III, SEMA3 species).…”