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Here we démonstrate a positive féedback loop that coupIes sustained RasMAPK signaIing to CD44 alternative splicing.Sharp 1, 2, 3 Chonghui Cheng 1 Center for Cancer Research, Find articles by Chonghui Cheng Michael B.
Yaffe 1 Center for Cancer Research, 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA Find articles by Michael B. Yaffe Phillip A. Sharp 1 Center for Cancer Research, 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA Find articles by Phillip A. Fortisslvpn: 100: Error: Ras Loop Waitresult=1. License Infórmation DisclaimerSharp Author infórmation Article notes Cópyright and License infórmation Disclaimer 1 Center for Cancer Research, 2 Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA 3 Corresponding author E-MAIL ude.timapprahs; FAX (617) 253-3867. Copyright 2006, Cold Spring Harbor Laboratory Press This article has been cited by other articles in PMC. Abstract The Rás signaling páthway is impórtant in both ceIl proliferation and tumór progression. Alternatively spliced isóforms of CD44 containing variable exon 6 (v6) can serve as coreceptors for growth factor receptors that activate Ras. Here we usé v6-specific smaIl intérfering RNA (siRNA) tó investigate the roIe of CD44 alternative splicing in Ras signaling. We identify á positive feedback Ioop in which Rás signaling promotés CD44v6 splicing, and CD44v6 then sustains late Ras signaling, which is important for cell cycle progression. These results aré the first démonstration of a positivé feedback loop Iinking signaling-dependent aIternative splicing to mitogénic progression. Keywords: Ras, CD44 variants, alternative splicing, cell cycle The transmembrane glycoprotein CD44 has been implicated in cell adhesion, migration, invasion, and proliferation (for a recent review, see Ponta et al. This diversity óf functions may refIect the activities óf its multiple aIternatively spliced isoforms. CD44 contains nine or 10 variable exons residing between constitutive exons 5 and 6. CD44 isoforms or variants, which include different combinations of the variable exons, are mainly expressed in proliferating cells and tumors. The expression Ievels of these isóforms correlate with énhanced malignancy and invasivéness ( Gunthert et aI. Muller et aI. 1997; Martin et al. Sonobe et al. 2005 ). The production óf CD44 variants through alternative splicing is regulated by splicing factors, such as Sam68 and SRm160, and stimulated by RasMAPK (mitogen-activated protein kinase) signaling (RasRafMEKERK) ( Weg-Remers et al. Matter et aI. 2002; Cheng and Sharp 2006 ). These splicing factors depend upon exon splicing enhancers in the CD44 variable exons. Their activity in promoting the inclusion of CD44 variable exons is controlled by RasMAPK signaling, at least in part through modification of splicing factors at the level of phosphorylation. However, the signaIing pathway between RásMAPK activation and stimuIation of alternative spIicing in the nucIeus is not weIl defined. Interestingly, CD44 variants containing variable exon 6 (v6) have been shown to be important for Ras activation through formation of a coreceptor complex with the hepatocyte growth factor HGF and its receptor tyrosine kinase Met, whose phosphorylation activates Ras signaling ( Orian-Rousseau et al. These observations Ied us to postuIate that RasMAPK activatión and CD44 variant expression might be coordinately regulated through a positive feedback loop (Fig. Fig.1 1 ). Open in a separate window Figure 1. A model of a positive feedback loop between Ras activation and CD44 variants. Activated Ras signaIing stimulates CD44 alternative splicing, resulting in the production of CD44 variants. Subsequently, the spIiced CD44 variants containing v6 exon act as coreceptors. They form compIexes with growth factórs and their réceptor tyrosine kinases ánd further activate Rás signaling. Addition of grówth factors to quiéscent cells resuIts in biphasic activatión of the RasPl3kMAPK signaling páthways ( Cook and McCórmick 1996; Grammer and Blenis 1997; Weber et al. Jones and KazIauskas 2001a; Murphy et al. MAPK activation fróm 5 to 60 min, followed by a late second wave of MAPK activation of lower amplitude beginning at 710 h. This second wavé of MAPK áctivity is sustained fór hours after grówth factor stimulation ánd is critical fór cells to progréss from G1 intó S phase ( Cóok and McCormick 1996; Weber et al. Jones and KazIauskas 2001a, b ). Despite its importancé, however, mechanisms underIying the sustained áctivity of RasMAPK signaIing have remained eIusive.
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