Abstract
BackgroundRASopathies are a group of syndromes showing clinical overlap caused by mutations in genes affecting the RAS-MAPK pathway. Consequent disruption on cellular signaling leads and is driven by phosphoproteome remodeling. However, we still lack a comprehensive picture of the different key players and altered downstream effectors.MethodsAn in silico interactome of RASopathy proteins was generated using pathway enrichment analysis/STRING tool, including identification of main hub proteins. We also integrated phosphoproteomic and immunoblotting studies using previous published information on RASopathy proteins and their neighbors in the context of RASopathy syndromes. Data from Phosphosite database (www.phosphosite.org) was collected in order to obtain the potential phosphosites subjected to regulation in the 27 causative RASopathy proteins. We compiled a dataset of dysregulated phosphosites in RASopathies, searched for commonalities between syndromes in harmonized data, and analyzed the role of phosphorylation in the syndromes by the identification of key players between the causative RASopathy proteins and the associated interactome.ResultsIn this study, we provide a curated data set of 27 causative RASopathy genes, identify up to 511 protein–protein associations using pathway enrichment analysis/STRING tool, and identify 12 nodes as main hub proteins. We found that a large group of proteins contain tyrosine residues and their biological processes include but are not limited to the nervous system. Harmonizing published RASopathy phosphoproteomic and immunoblotting studies we identified a total of 147 phosphosites with increased phosphorylation, whereas 47 have reduced phosphorylation. The PKB signaling pathway is the most represented among the dysregulated phosphoproteins within the RASopathy proteins and their neighbors, followed by phosphoproteins implicated in the regulation of cell proliferation and the MAPK pathway.ConclusionsThis work illustrates the complex network underlying the RASopathies and the potential of phosphoproteomics for dissecting the molecular mechanisms in these syndromes. A combined study of associated genes, their interactome and phosphorylation events in RASopathies, elucidates key players and mechanisms to direct future research, diagnosis and therapeutic windows.
Highlights
RASopathies are a group of syndromes showing clinical overlap caused by mutations in genes affect‐ ing the RAS-mitogen-activated protein kinase (MAPK) pathway
These disorders include neurofibromatosis type 1 (NF1), Legius syndrome (LS), Noonan syndrome (NS), neurofibromatosis-Noonan syndrome (NFNS), Noonan syndrome-like (NSL), Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, Noonan syndrome-like with loose anagen hair (NSLSH) known as Mazzanti syndrome, Costello syndrome (CS), cardiofaciocutaneous (CFC) syndrome, capillary malformation-arteriovenous malformation syndrome (CM-AVM), intellectual disability associated with autism spectrum disorder and juvenile myelomonocytic leukemia (JMML) [3,4,5]
The disorders include cardiofaciocutaneous (CFC), Costello syndrome (CS), juvenile myelomonocytic leukemia (JMML), Legius syndrome (LS), neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome-like (NSL), Noonan syndrome-like with loose anagen hair (NSLSH) and Noonan syndrome with multiple lentigines (NSML)
Summary
RASopathies are a group of syndromes showing clinical overlap caused by mutations in genes affect‐ ing the RAS-MAPK pathway. The RAS/ MAPK signaling pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA, and has major impact in human health [2,3,4] These disorders include neurofibromatosis type 1 (NF1), Legius syndrome (LS), Noonan syndrome (NS), neurofibromatosis-Noonan syndrome (NFNS), Noonan syndrome-like (NSL), Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, Noonan syndrome-like with loose anagen hair (NSLSH) known as Mazzanti syndrome, Costello syndrome (CS), cardiofaciocutaneous (CFC) syndrome, capillary malformation-arteriovenous malformation syndrome (CM-AVM), intellectual disability associated with autism spectrum disorder and juvenile myelomonocytic leukemia (JMML) [3,4,5]. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations have been reported [29, 39]
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