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. Author manuscript; available in PMC: 2021 Jun 4.
Published in final edited form as: Hum Genet. 2019 Dec 13;139(3):357–369. doi: 10.1007/s00439-019-02094-6

Figure 3: Regulation of alternative splicing by nutrient sensing signaling pathways.

Figure 3:

Examples of nutrient sensing factors, implicated in the mechanisms of aging and longevity, impacting splicing factor regulatory protein phosphorylation, localization and levels. Extracellular signals including insulin/IGF activate growth factor receptors and impact signaling to a number of different pathways. Activated Ras causes a signaling cascade that involves MAPK/ERK signaling to increase SRSF1 expression and subsequent increase in exon inclusion of the insulin receptor (INSR) transcript to form insulin receptor beta (INSR-B). PI3K signaling downstream of insulin increases AKT mediated phosphorylation of SR protein kinases (SRPKs) or SR proteins directly. Phosphorylation induces nuclear localization and can alter splicing of transcripts including PKC exon inclusion to form PKC beta isoform. Lastly, mTORC1 signaling increases phosphorylation of S6K which phosphorylates SRPK2 and leads to nuclear translocation. SRPK2 then phosphorylates SR proteins. The impact of these splicing regulatory factor-mediated changes in alternative splicing is alterations in isoform expression and cellular functions including lipogenesis and glucose uptake. Lastly, nutrient sensing and alternative splicing are important for survival in yeast as nutrient depletion leads to an accumulation of stable introns in a TORC1-dependent manner that protect cells from starvation by downregulating ribosomal biogenesis.