Abstract
The lipid- and protein phosphatase PTEN is one of the most frequently mutated tumor suppressor genes in human cancers and many mutations found in tumor samples directly affect PTEN phosphatase activity. In order to understand the functional consequences of these mutations in vivo, the aim of our study was to dissect the role of Pten phosphatase activities during zebrafish embryonic development. As in other model organisms, zebrafish mutants lacking functional Pten are embryonically lethal. Zebrafish have two pten genes and pten double homozygous zebrafish embryos develop a severe pleiotropic phenotype around 4 days post fertilization, which can be largely rescued by re-introduction of pten mRNA at the one-cell stage. We used this assay to characterize the rescue-capacity of Pten and variants with mutations that disrupt lipid, protein or both phosphatase activities. The pleiotropic phenotype at 4dpf could only be rescued by wild type Pten, indicating that both phosphatase activities are required for normal zebrafish embryonic development. An earlier aspect of the phenotype, hyperbranching of intersegmental vessels, however, was rescued by Pten that retained lipid phosphatase activity, independent of protein phosphatase activity. Lipid phosphatase activity was also required for moderating pAkt levels at 4 dpf. We propose that the role of Pten during angiogenesis mainly consists of suppressing PI3K signaling via its lipid phosphatase activity, whereas the complex process of embryonic development requires lipid and protein phosphatase of Pten.
Highlights
PTEN (Phosphatase and tensin homolog) is one of the most frequently mutated tumor suppressor genes in spontaneous cancers [1, 2] and germline mutations of PTEN have been associated with PTEN hamartoma tumor syndromes (PHTS), such as Cowden syndrome and BannayanRiley-Ruvalcaba syndrome [3,4,5], and with autism-spectrum disorders [6, 7]
We previously reported that zebrafish, as many other teleosts, have two pten genes, ptena and ptenb, that have redundant functions during embryonic development [9] and that both ptena and ptenb largely rescued the morphological defects in ptena-/-ptenb-/- zebrafish [43]
Address whether Pten lipid and protein phosphatase activity are required for correct embryonic development, we investigated the capacity of Pten mutants to functionally rescue the pleiotropic phenotype of ptena-/-ptenb-/- embryos
Summary
PTEN (Phosphatase and tensin homolog) is one of the most frequently mutated tumor suppressor genes in spontaneous cancers [1, 2] and germline mutations of PTEN have been associated with PTEN hamartoma tumor syndromes (PHTS), such as Cowden syndrome and BannayanRiley-Ruvalcaba syndrome [3,4,5], and with autism-spectrum disorders [6, 7]. Pten Lipid and Protein Phosphatase Activity in Zebrafish Development. A prominent function of the tumor suppressor PTEN is its lipid phosphatase activity towards phosphatidylinositol (3, 4, 5)-trisphosphate (PIP3), which makes PTEN the main antagonist of the cell proliferation and cell survival promoting phosphatidylinositol-3-kinase (PI3K)/ Akt ( known as protein kinase B, PKB) signaling pathway [13]. Little-known, in contrast, is its dual-specificity protein phosphatase activity against phosphotyrosine (pTyr), phosphoserine (pSer) and phosphothreonine (pThr), which was discovered and characterized [14] shortly after the identification of PTEN as one of the most frequently mutated tumor suppressor genes in human cancers. The main attention so far has been drawn to the lipid phosphatase activity of PTEN, partly due to the early identification of germ line mutations in PTEN in Cowden syndrome patients, that are affecting the protein’s lipid phosphatase activity [3, 15]
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