Dusp-5 and Snrk-1 coordinately function during vascular development and disease

Abstract

IntroductionThe mitogen-activated protein kinase (MAPK) pathway 1 represent a key signal integration step inside the cell for various extracellular stimuli. 2 At least 4 MAPK families have been identified: the extracellular signal-regulated kinases 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and Erk5. Each MAPK is activated by specific MAPK kinases (Mkks or Meks), which in turn are regulated by Mek kinases (Mekks). To date, several members of the MAPK family, including Erk5 3 and Mekk3, 4 have been implicated in vascular development in vivo. 5 Furthermore, MAPKs are often associated with pathologic responses, such as stress, apoptosis, inflammation, and cell proliferation. 5,6 In terms of vascular conditions, differential expression of active MAPKs was noticed in several types of hemangiomas, 7 the most common vascular tumor of infancy and childhood, 8 and the presence of immunoreactive phosphorylated MAPK inversely correlate with degree of malignancy. 7 Therefore, from a drug discovery standpoint, vascular specific components of MAPKs cascade are promising drug targets. 6 MAPKs are activated by dual phosphorylation of tyrosine and threonine residues in their activation loops. To control MAPK activation, a family of proteins called dual-specificity protein tyrosine phosphatases (DUSPs) dephosphorylate both residues. 9 DUSPs come in 2 varieties: dual-specificity MAPK phosphatases and atypical DUSPs. A dual specific phosphatase, Dusp-5, was recently identified by 2 independent microarray studies as a vascular-specific gene, 10,11 and we hypothesized that dusp-5 plays a specific role in vascular development. To investigate dusp-5 function, we initiated a loss-of-function (LOF) study in zebrafish (ZF). We identified that dusp-5 LOF embryos showed enhanced etsrp ϩ angioblasts at the lateral plate mesoderm (LPM). Recently, we had identified in a gain-of-function (GOF) and LOF study for a serine-threonine kinase member of the sucrose nonfermenting kinase family, Snrk-1, that it increased or decreased, respectively, the same etsrp ϩ angioblast population at the LPM. 12 Taking these findings together, we hypothesized that, during vascular development, Dusp-5 and Snrk-1 function together in controlling angioblast numbers at the LPM. In this study, we show that dusp-5 is expressed in angioblasts in the embryonic ZF and is essential for vascular development in vivo. We show that loss of Dusp-5 function in vitro causes apoptosis of endothelial cells (ECs), and Dusp-5 and Snrk-1 target a common signaling pathway responsible for maintaining angioblast populations along the LPM. Snrk-1 ectopically induces etsrp ϩ angioblasts in the LPM, which is blocked by Dusp-5 that functions downstream of Snrk-1. In addition, we have identified mutations in dusp-5 and snrk-1 in the lesional tissue of many vascular anomaly patient samples, suggesting a critical role for this pathway in disease. Methods ZF stocksWild-type ZF (TuAB strain) were grown and maintained at 28.5°C. 13 All procedures were performed according to animal protoc...

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“…Snrk is reported as a novel substrate for liver kinase B1 (29). It also controls angioblast populations in the lateral plate mesoderm in zebrafish (57). Usp9y is one of the major Y-linked spermatogenesis genes, which acts as a fine tuner to improve efficiency of human spermatogenesis (58).…”

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“…S3). This may be especially relevant considering the importance of dusp5 in vascular development (Pramanik et al, 2009). It also indicates that selectivity and specificity exist in the response of DUSPs to hypoxia.…”

Snrk-1 is involved in multiple steps of angioblast development and acts via notch signaling pathway in artery-vein specification in vertebrates

“…In an accompanying study, 21 we have identified mutations in snrk-1 in venous or lymphatic malformation patients. Therefore, it is feasible to propose that snrk-1 plays a central role in the pathogenesis of vascular anomalies.…”