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Semaphorin3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism

06/30/2011

Semaphorin3E-Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism

Jiha Kim, Won-Jong Oh, Nicholas Gaiano, Yutaka Yoshida, and Chenghua Gu

In this paper, Kim et al. reveal a novel mechanism by which the traditional axon guidance ligand-receptor guidance cues, Semaphorin 3E and Plexin-D1, directangiogenesis. Using the postnatal mouse retina as a model system, the authors found that the vascular endothelial growth factor (VEGF) limits the expression of Plexin-D1 to endothelial cells located at the front of actively sprouting blood vessels. VEGF-regulated Plexin-D1 expression thereby temporally and spatially restricts Sema3E-Plexin-D1 signaling, which, in turn, suppresses the VEGF-induced Dll4 -Notch signaling pathway. Ultimately, this negative feedback loop controls the balance of tip and stalk cells fate decisions and results in regulation of the retinal vascular network topology. 

The identification of Semaphorin3E-Plexin-D1 as a negative feedback regulator of VEGF has broad implications on the treatment of diseases involving angiogenesis such as diabetic retinopathy, neovascular macular degeneration, arthritis, as well as treatment of solid tumors and angiogenesis-dependent cancers. The authors emphasize that "because of the selective expression of Plexin-D1 only in ectopically formed vessels and not in mature established vessels of adulthood, agents that specifically target sema3E-Plexin-D1 signaling will provide a novel, effective and more specific treatment option for diseases involving angiogenesis, either used alone, combined with anti-VEGF therapy, or in therapies targeting the Notch signaling pathway."

Phosphorylation of H4 serine 47 promotes HIRA-mediated nucleosome assembly

Bin Kang Mintie Pu, Gangqing Hu, Weihong Wen, Zigang Dong, Keji Zhao, Bruce Stillman, and Zhiguo Zhang

Multiple histone H3 variants exist in mammalian cells. While histone variant H3.3 differs from the canonical histone H3 (H3.1) by only five amino acids, it has distinct roles in heterochromatin formation and gene silencing. It is also packaged into nucleosomes via a distinct mechanism: H3.1-H4 is assembled via a CAF-1-mediated and replication-coupled process, while H3.3-H4 is assembled via HIRA and Daxx in a replication-independent process.

In this paper, Kang et al. reveal that a single post-translational modification on histone H4 differentially regulates these distinct nucleosome assembly pathways.

The authors demonstrate that phosphorylation of histone H4 serine 47 (H4S47ph), which is catalyzed by the PAK2 kinase, promotes HIRA-mediated nucleosome assembly and inhibits the CAF-1-mediated pathway. According to their data, H4S47ph increases the association of HIRA with H3.3-H4 and inhibits the association of CAF-1 with H3.1-H4.

 

PAK2 is an auto-inhibitory kinase that is activated in response to external cellstimuli. The authors point out that, "our results, for the first time, link a kinase involved in cell signaling to the regulation of two important nucleosome assembly pathways in mammalian cells, and imply that nucleosome assembly ofH3.3 and H3.1 is dynamically regulated in response to environmental cures."

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