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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4153-4154. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Claesson-Welsh, L. Search for Related Content PubMed Articles by Claesson-Welsh, L. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Next Article  HEMOSTASIS Comment on Conrotto et al, page 4321 Novel paths to blood vessel formation Lena Claesson-Welsh UPPSALA UNIVERSITY Semaphorins are known to negatively regulate blood vessel formation, for example, by antagonizing endothelial cell integrins. Conrotto and colleagues now demonstrate that semaphorins may also be endowed with proangiogenic properties. Intense work in recent years has shown that angiogenesis is guided by repellant cues provided by certain members of the semaphorin family of transmembrane, glycosylphosphatidyl-inositol (GPI)–anchored, and secreted proteins. Semaphorins act through plexins, transmembrane molecules thought to be equipped with intrinsic GTPase-activating protein (GAP) activity. In their exciting study published in this issue of Blood, Conrotto and colleagues now present evidence that certain semaphorins provide attracting cues to endothelial cells: exposure of endothelial cells to Sema4D, expressed in secreted or transmembrane forms, leads to endothelial cell migration and sprouting but not mitogenicity, in a manner dependent both on the Sema4D receptor Plexin B1, and the receptor tyrosine kinase Met, but independent of the natural Met ligand, scatter factor/hepatocyte growth factor. It is noteworthy that Sema4D, Plexin B1, and Met share structural motifs in their extracellular domains, including a 500-amino acid residue Sema domain and a cystein-rich stretch of 80 amino acid residues. The work by Controtto et al demonstrates a novel angiogenic pathway leading to formation of vessels apparently indistinguishable from those induced by conventional angiogenic factors such as vascular endothelial growth factor (VEGF). This intriguing new pathway displays several facets of specificity: First, other semaphorins such as Sema3A, Sema4B, or Sema6A do not induce endothelial cell sprouting or chicken embryo angiogenesis. Furthermore, there is no cross-talk between the Sema4D pathway and vascular endothelial growth factor VEGF-induced angiogenesis, or at least, VEGF is not up-regulated by Sema4B and blocking Plexin B1 or Met function does not affect VEGF-induced angiogenesis. Moreover, the Sema4/Plexin B1/Met-induced angiogenesis does not involve Rho/Rho kinases, which have been shown to be critical in VEGF-induced actin reorganization, migration, and angiogenesis.1 Another level of specificity is illustrated by the Met-dependent signals emitted through Sema4B-binding to plexin B1, which lead to actin reorganization and migration but not mitogenicity (see figure). This resembles the contribution of neuropilin-1 to VEGF/VEGFR-2 signaling, which leads to augmented moto- but not mitogenicity.2 Individually, both Plexin B1 (in B lymphocytes) and Met (in endothelial and epithelial cells) are capable of transducing mitogenic responses. The nature of signals transduced by the Sema4D-activated Plexin B1/Met complex leading to cell migration, as well as the extent to which both components, Plexin B1 and Met, directly contribute to the signaling, remain to be explored. The general concept of signaling by receptor tyrosine kinases such as Met is well established and known to involve dimerization of receptor molecules, allowing phosphorylation in trans of positive regulatory tyrosine residues. It is likely that complex formation with Sema4D/Plexin B1 induces formation of Met dimers, but these have different properties than those induced by the natural Met ligand, scatter factor. Possibly, Met dimers induced by Sema4D/Plexin B1 are less stable or the pattern of trans phosphorylation is different, both of consequence for signal transduction. These are exciting and challenging subjects that need to be addressed for us to understand this novel path to blood vessel formation. View larger version (61K): [in this window] [in a new window]   Binding of scatter factor (SF) to the extracellular domain of Met expressed in endothelial cells leads to receptor dimerization and signals to migration and proliferation and eventually, angiogenesis. Clustering of Sema4D-bound Plexin B1 induces Met dimerization in the absence of scatter factor and transduction of proangiogenic signals involving cell migration but not proliferation.   References Hoang MV, Whelan MC, Senger DR. Rho activity critically and selectively regulates endothelial cell organization during angiogenesis. Proc Natl Acad Sci U S A. 2004;101: 1874-1879.[Abstract/Free Full Text] Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998;92: 735-745.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Sema4D induces angiogenesis through Met recruitment by Plexin B1 Paolo Conrotto, Donatella Valdembri, Simona Corso, Guido Serini, Luca Tamagnone, Paolo Maria Comoglio, Federico Bussolino, and Silvia Giordano Blood 2005 105: 4321-4329. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Claesson-Welsh, L. Search for Related Content PubMed Articles by Claesson-Welsh, L. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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