The kinase Mnk2 is a substrate of the MAPK pathway and phosphorylates the translation initiation factor eIF4E. In humans,MKNK2, the gene encoding for Mnk2 is alternatively spliced yielding two splicing isoforms with differing last exons: Mnk2a, which contains a MAPK binding domain and Mnk2b which lacks it. We found that the Mnk2a isoform is downregulated in breast, lung and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates and translocates p38α into the nucleus leading to activation of its target genes, increasing cell death and suppression of Ras-induced transformation in vitro and in vivo. Alternatively, Mnk2b which is upregulated in many tumors, is pro-oncogenic and does not activate p38-MAPK while enhancing eIF4E phosphorylation. Furthermore, we show that elevation of the splicing factor SRSF1 by oncogenic Ras modulates Mnk2 alternative splicing to downregulate the tumor suppressive isoform Mnk2a and upregulate Mnk2b. Thus, Mnk2a downregulation by alternative splicing is a new tumor suppressor mechanism which is lost in breast, colon and lung cancers and is regulated by Ras.