title: Mysteries of TGF-β Paradox in Benign and Malignant Cells.
abstract: TGF-β regulates a wide range of biological functions including embryonic development, wound healing, organogenesis, immune modulation, and cancer progression. Interestingly, TGF-β is known to inhibit cell growth in benign cells but promote progression in cancer cells; this phenomenon is known as TGF-β paradox. To date, the mechanism of this paradox still remains a scientific mystery. In this review, we present our experience, along with the literature, in an attempt to answer this mystery. First, we observed that, on TGF-β engagement, there is a differential activation of Erk between benign and cancer cells. Since activated Erk is a major mediator in tumor progression and metastasis, a differentially activated Erk represents the answer to this mystery. Second, we identified a key player, PP2A-B56α, which is differentially recruited by the activated type I TGF-β receptor (TBRI) in benign and tumor cells, resulting in differential Erk activation. Finally, TGF-β stimulation leads to suppressed TBRs in tumor cells but not in benign cells. This differentially suppressed TBRs triggers differential recruitment of PP2A-B56α and, thus, differential activation of Erk. The above three events explain the mysteries of TGF-β paradox. Understanding the mechanism of TGF-β paradox will help us to predict indolent from aggressive cancers and develop novel anti-cancer strategies.
authors.affiliation: Department of Urology, Northwestern University School of Medicine , Chicago, IL , USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Urology, General Hospital of Jinan Military Command , Jinan , China.
authors.forename: Nengwang
authors.initials: N
authors.lastname: Yu
authors.affiliation: Department of Urology, Northwestern University School of Medicine , Chicago, IL , USA ; Department of Surgery, NorthShore University HealthSystem, Evanston Hospital , Evanston, IL , USA ; Department of Pathology and Laboratory Medicine, University of California at Irvine , Irvine, CA , USA ; Department of Urology, University of California at Irvine , Irvine, CA , USA.
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
keywords: Erk activation; PP2A recruitment; Smad activation; TGF-β auto-induction; TGF-β paradox; TGF-β receptors; negative feedback; positive feedback