Novel permissive role of epidermal growth factor in transforming growth factor β (TGF-β) signaling and growth suppression -: Mediation by stabilization of TGF-β receptor type II

Transforming growth factor beta (TGF-beta) signals through TGF-beta receptor serine/threonine kinases (T beta RI and T beta RII) and Smads, regulating cell growth and apoptosis. Although loss of TGF-beta receptor levels is strongly selected for during the progression of most cancers, tumor cells frequently escape from complete loss of TGF-beta receptors through unknown mechanisms. Here, we provide the first evidence that epidermal growth factor (EGF) signaling, which is generally enhanced in cancer, is permissive for regulation of gene expression and growth suppression by TGF-beta in LNCaP prostate adenocarcinoma cells. Our results support that these permissive effects occur through enhanced stability of T beta RII mRNA and reversal of TGF-beta-mediated T beta RII mRNA loss. Changes in stability of T beta RII mRNA occur soon after EGF or TGF-beta 1 addition ( optimal within 3 h) and are independent of de novo protein synthesis or transcription. Remarkably, such loss of T beta RII by TGF-beta can be mediated by a kinase-dead T beta RII (K277R), as well as by other forms of this receptor harboring mutations at prominent autophosphorylation sites. Moreover, Smad3 small interfering RNA, which blocks TGF-beta-induced AP-1 promoter activity, does not block changes in the expression of T beta RII by EGF or TGF-beta. We have also shown that changes in T beta RII levels by EGF are EGF receptor-kinase-dependent and are controlled by signals downstream of MEK1/2. Our findings provide invaluable insights on the role of the EGF receptor-kinase in enhancing TGF-beta responses during prostate carcinogenesis.