EGF stimulates large-scale splicing changes via AKT and SR protein kinase signaling.
Major finding: EGF stimulates large-scale splicing changes via AKT and SR protein kinase signaling.
Mechanism: Activated AKT promotes SRPK1 autophosphorylation and HSP90-mediated nuclear translocation.
Impact: Altered SRPK expression may contribute to tumor growth through modulation of splicing.
Alternative splicing of pre-mRNA is a key modulator of gene expression, and several cellular signaling molecules have been implicated in the regulation of this process, including members of the PI3K/AKT pathway and SR protein kinases (SRPK), which phosphorylate essential splicing regulatory factors. However, the detailed mechanism connecting AKT to upstream growth factors and downstream effector proteins is not well understood. Zhou and colleagues describe a pathway by which epidermal growth factor (EGF) signaling is transduced through AKT and SRPKs to promote changes in splicing. EGF treatment induced a marked reprogramming of splicing that was dependent on PI3K signaling and the kinase activity of AKT. In addition, EGF-regulated splicing was abrogated in the absence of SRPK expression but was not affected by inhibition of mTOR, suggesting that a PI3K/AKT signaling branch through SRPKs is essential for this phenomenon. Binding of activated AKT to SRPK1 stimulated the phosphorylation of wild-type, but not kinase-dead, SRPK1, suggesting that AKT induces SRPK1 autophosphorylation and that this modification may be important for SRPK1 function. In support of this idea, mutation of SRPK1 phosphorylation sites to alanine prevented a shift in splice-site selection, whereas a phospho-mimetic mutant of SRPK1 enhanced alternative splicing efficiency independent of PI3K/AKT activation. Furthermore, autophosphorylation of SRPK triggered a switch in SRPK complex formation with molecular chaperones, resulting in decreased association with HSP70 and increased binding to HSP90 upon EGF stimulation. Interaction of SRPKs with HSP90 facilitated nuclear translocation of these kinases and subsequent hyperphosphorylation of target splicing effector proteins. Taken together, these results identify a signal transduction pathway that is important for the control of splicing and suggest that altered SRPK expression may play a role in tumorigenesis by inducing changes in mRNA isoform selection.
Zhou Z, Qiu J, Liu W, Zhou Y, Plocinik RM, Li H, et al. The Akt-SRPK-SR axis constitutes a major pathway in transducing EGF signaling to regulate alternative splicing in the nucleus. Mol Cell 2012;47:1–12.
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