Research ArticleAngiogenesis

The Akt1-eNOS Axis Illustrates the Specificity of Kinase-Substrate Relationships in Vivo

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Science Signaling  04 Aug 2009:
Vol. 2, Issue 82, pp. ra41
DOI: 10.1126/scisignal.2000343

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Defining the Critical Relationship

Many protein kinases have multiple potential substrates and, in turn, many substrate sites can be phosphorylated by multiple kinases. Thus, determining which of many possible kinase-substrate pairs mediate a particular response can be challenging. Here, Schleicher et al. used lines of mice that both lacked the protein kinase Akt1 and carried mutations in the Akt1 substrate endothelial nitric oxide synthase (eNOS) that either mimicked or abolished Akt1 phosphorylation to tease out the physiological functions of Akt1-eNOS signaling. Although various phenotypes associated with loss of Akt1 were unaffected by the eNOS mutations—indicating that these Akt1 functions were mediated through other substrates—defects in postnatal reparative angiogenesis associated with the loss of Akt1 were rescued by the phosphomimetic mutant. Further analysis indicated that Akt1 signaled through eNOS to regulate the hypoxia-inducible factor 1α (HIF-1α)–mediated angiogenic response to ischemia. Thus, the authors conclude that Akt1 regulates postnatal angiogenesis largely through eNOS phosphorylation.

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