IQGAP1 (
IQ motif-containing GTPase-activating protein 1) scaffolds several signaling pathways in mammalian cells that are implicated in
carcinogenesis, including the RAS and PI3K pathways that involve multiple
protein kinases. IQGAP1 has been shown to promote
head and neck squamous cell carcinoma (
HNSCC); however, the underlying mechanism(s) remains unclear. Here, we report a mass spectrometry-based analysis identifying differences in phosphorylation of cellular
proteins in vivo and in vitro in the presence or absence of IQGAP1. By comparing the esophageal phosphoproteome profiles between Iqgap1+/+ and Iqgap1-/- mice, we identified RNA splicing as one of the most altered cellular processes.
Serine/
arginine-rich
splicing factor 6 (SRSF6) was the
protein with the most downregulated levels of phosphorylation in Iqgap1-/- tissue. We confirmed that the absence of IQGAP1 reduced SRSF6 phosphorylation both in vivo and in vitro. We then expanded our analysis to human normal oral keratinocytes. Again, we found factors involved in RNA splicing to be highly altered in the phosphoproteome profile upon genetic disruption of IQGAP1. Both the Clinical Proteomic
Tumor Analysis Consortium (CPTAC) and the
Cancer Genome Atlas (TCGA) data sets indicate that phosphorylation of splicing-related
proteins is important in
HNSCC prognosis. The
Biological General Repository for Interaction Datasets (BioGRID) repository also suggested multiple interactions between IQGAP1 and splicing-related
proteins. Based on these collective observations, we propose that IQGAP1 regulates the phosphorylation of splicing
proteins, which potentially affects their splicing activities and, therefore, contributes to
HNSCC. Raw data are available from the MassIVE database with identifier MSV000087770.