SR Protein Kinases Regulate Molecular Pathway Controlling Alternative mRNA Splicing

A paper described the discovery of a molecular signaling pathway that regulates the process known as alternative mRNA splicing.

Alternative splicing is a process by which the exons of the RNA produced by transcription of a gene are reconnected in multiple ways during RNA splicing. The resulting different mRNAs may be translated into different protein isoforms, thereby allowing a single gene to code for multiple proteins. Alternative splicing occurs as a normal phenomenon in eukaryotes, where it greatly increases the biodiversity of proteins that can be encoded by the genome. In humans, about 95% of multiexonic genes are alternatively spliced. Numerous modes of alternative splicing have been observed, of which the most common is exon skipping. In this mode, a particular exon may be included in mRNAs under some conditions or in particular tissues, and omitted from the mRNA in others. Abnormal variations in splicing have also been implicated in disease, since a large proportion of human genetic disorders result from splicing variants. Abnormal splicing variants are also thought to contribute to the development of cancer.

Pre-mRNA splicing is regulated by developmental and environmental cues, but little has been known about how specific signals are transduced in mammalian cells to regulate this critical gene expression step. Now investigators at the University of California, San Diego (USA) have contributed substantially to our understanding of how alternative splicing is regulated.

They reported in the June 21, 2012, online edition of the journal Molecular Cell that molecular cues such as EGF (epidermal growth factor) signaling triggered the massive activation of Akt (protein kinase B). Activated Akt next branched to SR protein-specific kinases - serine/arginine-rich proteins that are involved in regulating and selecting splice sites in eukaryotic mRNA - rather than mTOR (mammalian target of rapamycin), by inducing SRPK autophosphorylation. This led to enhanced SRPK nuclear translocation and SR protein phosphorylation.

“The kinase sits right in the middle of the PI3K-Akt pathway to specifically relay the growth signal to regulate alternative splicing in the nucleus,” said senior author Dr. Xiang-Dong Fu, professor of cellular and molecular medicine at the University of California, San Diego. “It is a new signaling branch that has previously escaped detection. It is a good target because of its central role and because it can be manipulated with compounds that suppress its activity, which appears quite effective in suppressing blood vessel formation in cancer.”

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