A positive feedback loop couples Ras activation and CD44 alternative splicing

The Ras signaling pathway is important in both cell proliferation and tumor progression. Alternatively spliced isoforms of CD44 containing variable exon 6 (v6) can serve as coreceptors for growth factor receptors that activate Ras. Here we use v6-specific small interfering RNA (siRNA) to investigate the role of CD44 alternative splicing in Ras signaling. We identify a positive feedback loop in which Ras signaling promotes CD44v6 splicing, and CD44v6 then sustains late Ras signaling, which is important for cell cycle progression. These results are the first demonstration of a positive feedback loop linking signaling-dependent alternative splicing to mitogenic progression.