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2 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Serini et al. 2. SEMAPHORINS, PLEXINS AND NEUROPILINS Firstly identified as chemorepulsive axon guidance cues, Sema constitute one of the largest phylogenetically conserved family of pleiotropic molecules acting in a wide range of biological processes, including central and peripheral nervous system development and regeneration, cardiovascular development, and immune system function [8, 9]. Sema are charatecerized by the presence of five specific types of domain: a ~500- amino-acid conserved Sema domain that constitutes the family hallmark, PSI (plexins, semaphorins and integrins) domains, Ig-like Class 1 Class 2 Class 3 Class 4 Class 5 Class 6 Class 7 viral SEMA Domain lg Domain Basic Domain CD72 Thrombospondin domain PSI domain domains, thrombospondin domains and a basic Cterminal domain. Eight different classes have been described: classes 1,2 and 5 in invertebrates; classes 3, 4,6 and 7 in vertebrates; class V classifies virally encoded proteins. Some classes (1,4,5,6 and 7) are characterized by membrane-bound molecules (transmembrane or glycosyl - phosphatidylinositol linked), while classes 2, 3 contain secreted Sema. Some membrane-associated semaphorins are proteolytically cleaved to generate soluble proteins, generating further diversity [reviewed in ([8, 9]] (Fig. 1). By far the most prominent Sema receptors are the Plx proteins. Plx are large conserved transmembrane PlxA PlxA or PlxD PlxB PlxB PlxA Tim-2 Integrin b1 PSI domain GTPase domain SEMA domain G-P rich motif GAP domain Fig. (1). Semaphorins and their receptors. Sema include transmembrane, secreted, and glycosyl phosphatidyl-inositol -linked proteins, most of which bind to Plx receptors. Class 1 and 2 and Sema5c Sema are invertebrate, and class 1 and 2 Sema utilize PlexA and PlexB receptors. The coreceptor D-OTK functions with PlexA. Sema in classes 3–7 are found in vertebrates. Class 3 and 6 Sema utilize PlexA receptors; however, most Sema3s require an obligate Nrp coreceptor. Sema6s interact directly with PlexAs. Other coreceptors that can function with PlexAs are L1CAM (L1 cell adhesion molecule), VEGFR2, and Offtrack. Class 4 and 5 Sema associate with PlexB1–3, and the receptor tyrosine kinases Met and ErbB2 can function as a coreceptor with PlexBs for certain class 4 Sema functions. Class 4 Sema directly bind to CD72 or Tim-2 in the immune system. Sema7A and a viral sema function together with PlexC1, and Sema7A also utilizes 1 integrin. PlxB PlxC
Plexins and Neuropilins Regulate Integrin Recent Advances in Angiogenesis and Antiangiogenesis, 2009 3 belonging to four classes (A–D), contain a divergent extracellular Sema domain and a conserved cytoplasmic domain unique to Plx with sequence similarity to a group of Ras-family-specific GTPaseactivating protein (GAP) activity. In addition to Plx, Sema holoreceptor complexes contain numerous coreceptors. Some of them are modulatory subunits (for example, Ig superfamily cell adhesion molecules), or provide further diversity to semaphorin function, such as such as CD72, T cell immunoglobulin and mucin-domain-containing 2 (Tim-2), vascularendothelial growth factor (VEGF) receptor R-2, c-Met and Erb-2 receptors, tyrosine kinase- like transmembrane protein offtrack or integrins [10-15]. However, most secreted Sema, including Sema3A and Sema3F do not bind directly to Plx receptors, but they use Nrp-1 or Nrp-2 as coreceptor ligand-binding subunits [16]. Interestingly, Nrp-1 and -2 are coreceptors of VEGFR-1,-2 and -3 engaged by different VEGF forms [17-19]. The extracellular region of Nrp1 contains two repeated complementbinding domains (CUB domains; a1–a2 domains), two coagulation factor-like domains (b1–b2 domains), and a juxtamembrane 5 meprin/A5/μ-phosphatase (MAM) homology domain. The Nrp1 intracellular region is only 50 amino acids long, and its function is poorly characterized [8, 9]. Domains b1-b2 have been implicated in the binding with VEGF-A165 [20], a1a2 and b1-b2 domains with Sema3A. The MAM/c domain instead mediates the Sema3A elicited Nrp1 oligomerization [8, 9] that is required for Sema3A SEMA binding VEGF binding/ Sema binding Clusterization 1 2 45% 48% 35% 55% MAM domain CUB (a1,a2) FVI / FVII (b1,b2) Fig. (2). Neuropilins structure. For details see text. Numbers indicate the homology percentage between Nrp-1 and Nrp-2. biological activity. The cytoplasmic tail includes about 42–44 amino acids and does not display catalytic activity of its own, but presents a binding site for the PDZ domain of Nrp-1-interacting protein [21] (Fig. 2). 3. ROLE OF SEMAPHORINS IN VAS- CULAR SYSTEM The first evidences for a role of Sema/Nrp/Plx system in vascular biology were provided by the groups Klagsbrun and Fujisawa, which respectively demonstrated that in ECs Nrp-1 acts a VEGFR-2 coreceptor [19] and found that Nrp-1 is required for mouse cardiovascular development [22]. Afterwards, several reports confirmed and extended these observations. In zebrafish, knockdown of sema3aa affects the migration of Nrp-1 + angioblasts, finally impairing dorsal aorta formation and normal circulation [23]. Additionally, single morpholino knockdown of either sema3aa or sema3ab in TG(fli1:EGFP) y1 embryos results in a less dramatic phenotype with patterning defects of intersomitic vessels [24]. Knockdown of Sema3a gene in outbred CD-1 mouse strain and over-expression of dominant negative Sema3 receptor mutants [25] or delivery of anti-Sema3A antibodies [26] in chick embryos were found to cause angiogenic remodeling defects. By studying the positive effect exerted by a specific Sema3A inhibitor in axonal regeneration into the injured spinal cord it has been observed an enhancement of angiogenesis in the injured tissue, reinforcing the concept of the negative modulatory role of Sema3A in angiogenesis [27]. In ECs PlxD1[28] and, albeit to lesser extent, PlxA2 [29] are the most abundant Plxs. Both Sema3A and Sema3C bind with a significantly higher affinity to a receptor complex formed by the association of Nrp-1 and/or -2 with PlxD1 than to a complex in which Nrps associates with PlxA1 [28]. Therefore, the Nrp/PlxD1 complex could represent the most efficient transducer of the chemorepulsive effect of Sema3A [30, 31]. Different from other Sema3, Sema3E can directly bind to PlxD1 [32]. Mainly based on defects in the intersomitic vessel patterning of Sema3E and PlxD1, Sema3E/PlxD1 has been proposed to be the major signaling pathway regulating vascular development [32, 33]. However, while Sema3e null mice are viable and do not show any gross abnormality [32], all PlxD1 -/- pups become cyanotic shortly after birth and succumb within 24 hrs because of severe cardiovascular defects [28]. Therefore, it is likely that in ECs PlxD1 transduces signals not only from Sema3E, but also from other Sema3 likely employing Nrp as co-receptors, as originally proposed by Epstein and colleagues [28]. Based on the fact that ECs express high levels of both Nrp1 and PlxD1 and on observations that Sema3E promotes tumor angiogenesis [34, 35], at present these
Page 2 and 3: Recent Advances in Angiogenesis and
Page 4 and 5: FOREWORD It has been known for a ve
Page 6 and 7: single proangiogenic protein. Howev
Page 8 and 9: v Vito Pistoia Head, Laboratory of
Page 12 and 13: 10 Recent Advances in Angiogenesis
Page 16 and 17: The Role of Mesenchymal Stem Cells
Page 22 and 23: Thymus and Angiogenesis Recent Adva
Page 32 and 33: Role of Thymidine Recent Advances i
Page 34 and 35: Role of Stromal Cells Recent Advanc
Page 40 and 41: Tumor Targeting with Transgenic End
Page 44 and 45: Tumor Vascular Disrupting Agents Re
Page 50 and 51: Tumour Vascular Disrupting Agents R
Page 52: Index Recent Advances in Angiogenes

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