Sema4D induces angiogenesis through Met recruitment by Plexin B1

Abstract

Semaphorins, a large family of membranebound and secreted proteins, signal through their transmembrane receptors, the plexins. Semaphorins and plexins share structural homologies with scatter factor receptors, a family of tyrosine kinase receptors for which Met is the prototype. Semaphorins have been studied primarily in the developing nervous system, where they act as repelling cues in axon guidance. However, they are widely expressed in several tissues, and their role in epithelial morphogenesis has been recently established. Not much is known about their role in angiogenesis, a key step during embryonic development and adulthood. Here we demonstrate that a semaphorin, Sema4D, is angiogenic in vitro and in vivo and that this effect is mediated by its high-affinity receptor, Plexin B1. Moreover, we prove that biologic effects elicited by Plexin B1 require coupling and activation of the Met tyrosine kinase. In sum, we identify a proangiogenic semaphorin and provide insight about the signaling machinery exploited by Plexin B1 to control angiogenesis. IntroductionSemaphorins belong to a large family of transmembrane, glycosylphosphatidylinositol (GPI)-anchored, and secreted proteins that have been divided into subclasses according to their structural features. 1 Semaphorins act by binding their cognate receptors, the plexins, a family of transmembrane molecules sharing structural homology with semaphorins themselves. 2 All plexins have a large cytoplasmic domain, highly conserved during evolution, that is endowed with R-Ras GAP activity 3 and is able to interact, directly or indirectly, with small G proteins, thus exerting control over cytoskeletal structures. [4][5][6][7] Semaphorins were originally characterized in the nervous system, where they are involved in the establishment of a correct neuronal network, steering axon growth cones and dendrites to their final targets. 8 According to the widespread expression of semaphorins and plexins, an increasing amount of data involve these 2 protein families in the development of different tissues and organs beyond the nervous system. In particular, a significant role for these molecules has been established in cardiac and skeletal development, 9 immune response, 10,11 epithelial morphogenesis, 12 and tumor growth and metastasis. 13,14 Although secreted class 3 semaphorins have been involved in the control of endothelial cell (EC) adhesion, motility, and vascular development, the role of semaphorins belonging to other classes remains largely unknown. Indeed, it has been shown that the prototypic secreted class 3 semaphorin, Sema3A, inhibits EC migration and in vitro angiogenesis. 15 Furthermore, during vascular development and experimental angiogenesis, ECs generate autocrine chemorepulsive signals, driven by class 3 semaphorins, that inhibit integrin activity, thus endowing the vascular system with the plasticity required for reshaping. 16 We focused our interest on Sema4D, a semaphorin originally identified for its activity in the immune system, where it promotes B ...

Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

“…Among them, plexin-B1 is a receptor for Sema4D, and it has been reported that Sema4D-Plexin-B1 signaling promotes endothelial cell migration and tube formation [67,68]. Interestingly, Sema4D expression is upregulated in head and neck squamous cell carcinoma as well as in some other solid tumors [69,70].…”

Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment

“…Notably, binding of Sema 4D to Plexin B1 transactivates the tyrosine kinase activity of cMet independent of the presence of HGF/SF [88]. Interestingly, the identical signaling pathway in endothelial cells leads to angiogenesis [89].…”

CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells

“…Another study showed that Sema4D induces angiogenesis, which was mediated by the coupling of its high-affinity receptor plexin-B1 with the Met tyrosine kinase (Conrotto et al, 2005). In addition, class IV semaphorins frequently have PDZ {PSD (postsynaptic density protein) 95, DlgA (Discs large A), and ZO (zonula occludens) 1)} domain-binding motifs at their C-termini, through which they may function as receptors by mediating signal transfers through their intracellular domains.…”