The Scaffold Protein IQGAP1 Links Heat-Induced Stress Signals to Alternative Splicing Regulation in Gastric Cancer Cells

In response to oncogenic signals, Alternative Splicing (AS) regulators such as SR and hnRNP proteins show altered expression levels, subnuclear distribution and/or post-translational modification status, but the link between signals and these changes remains unknown. Here, we report that a cytosolic scaffold protein, IQGAP1, performs this task in response to heat-induced signals. We show that in gastric cancer cells, a nuclear pool of IQGAP1 acts as a tethering module for a group of spliceosome components, including hnRNPM, a splicing factor critical for the response of the spliceosome to heat-shock. IQGAP1 controls hnRNPM's sumoylation, subnuclear localisation and the relevant response of the AS machinery to heat-induced stress. Genome-wide analyses reveal that IQGAP1 and hnRNPM co-regulate the AS of a cell cycle-related RNA regulon in gastric cancer cells, thus favouring the accelerated proliferation phenotype of gastric cancer cells. Overall, we reveal a missing link between stress signals and AS regulation. InfrafrontierGR/Phenotypos Infrastructure, co-funded by Greece and the European Union (European Regional Development Fund) [NSRF 2014–2020, MIS 5002135]; Hellenic Foundation for Research & Innovation (HFRI) and the General Secretariat for Research and Technology (GSRT) [grant agreement 846 to ZE]; MR was supported by the European Research Council [ERC AdvG 670146]; European Commission Grant FP7-PEOPLE-2010-IEF [274837] to PK; Stavros Niarchos Foundation (SNF) donation to BSRC “Al. Fleming”.