Non-Smad signaling pathways
Transforming growth factor-beta (TGFβ) is a key regulator of cell fate during embryogenesis and has also emerged as a potent driver of the epithelial-mesenchymal transition during tumor progression. TGFβ signals are transduced by transmembrane type I and type II serine/threonine kinase receptors (TβRI and TβRII, respectively). The activated TβR complex phosphorylates Smad2 and Smad3, converting them into transcriptional regulators that complex with Smad4. TGFβ also uses non-Smad signaling pathways such as the p38 and Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathways to convey its signals. Ubiquitin ligase tumor necrosis factor (TNF)-receptor-associated factor 6 (TRAF6) and TGFβ-associated kinase 1 (TAK1) have recently been shown to be crucial for the activation of the p38 and JNK MAPK pathways. Other TGFβ-induced non-Smad signaling pathways include the phosphoinositide 3-kinase-Akt-mTOR pathway, the small GTPases Rho, Rac, and Cdc42, and the Ras-Erk-MAPK pathway. Signals induced by TGFβ are tightly regulated and specified by post-translational modifications of the signaling components, since they dictate the subcellular localization, activity, and duration of the signal. In this review, we discuss recent findings in the field of TGFβ-induced responses by non-Smad signaling pathways.
KeywordsNon-Smads Smads TAK1 TGFβ TRAF6
We thank Carl-Henrik Heldin for comments on our review, and we are grateful to all the past and present members of the apoptotic signaling group for their contributions to the scientific endeavors of our laboratory.
- Bettermann K, Vucur M, Haybaeck J, Koppe C, Janssen J, Heymann F, Weber A, Weiskirchen R, Liedtke C, Gassler N, Muller M, Vos R de, Wolf MJ, Boege Y, Seleznik GM, Zeller N, Erny D, Fuchs T, Zoller S, Cairo S, Buendia MA, Prinz M, Akira S, Tacke F, Heikenwalder M, Trautwein C, Luedde T (2010) TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell 17:481–496PubMedCrossRefGoogle Scholar
- DiVito KA, Trabosh VA, Chen YS, Chen Y, Albanese C, Javelaud D, Mauviel A, Simbulan-Rosenthal CM, Rosenthal DS (2010) Smad7 restricts melanoma invasion by restoring N-cadherin expression and establishing heterotypic cell-cell interactions in vivo. Pigment Cell Melanoma Res 23:795–808PubMedCrossRefGoogle Scholar
- Dupont S, Mamidi A, Cordenonsi M, Montagner M, Zacchigna L, Adorno M, Martello G, Stinchfield MJ, Soligo S, Morsut L, Inui M, Moro S, Modena N, Argenton F, Newfeld SJ, Piccolo S (2009) FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination. Cell 136:123–135PubMedCrossRefGoogle Scholar
- Edlund S, Bu S, Schuster N, Aspenstrom P, Heuchel R, Heldin NE, Dijke P ten, Heldin CH, Landstrom M (2003) Transforming growth factor-beta1 (TGF-beta)-induced apoptosis of prostate cancer cells involves Smad7-dependent activation of p38 by TGF-beta-activated kinase 1 and mitogen-activated protein kinase kinase 3. Mol Biol Cell 14:529–544PubMedCrossRefGoogle Scholar
- Greenblatt MB, Shim JH, Zou W, Sitara D, Schweitzer M, Hu D, Lotinun S, Sano Y, Baron R, Park JM, Arthur S, Xie M, Schneider MD, Zhai B, Gygi S, Davis R, Glimcher LH (2010) The p38 MAPK pathway is essential for skeletogenesis and bone homeostasis in mice. J Clin Invest 120:2457–2473PubMedCrossRefGoogle Scholar
- Groppe J, Hinck CS, Samavarchi-Tehrani P, Zubieta C, Schuermann JP, Taylor AB, Schwarz PM, Wrana JL, Hinck AP (2008) Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol Cell 29:157–168PubMedCrossRefGoogle Scholar
- Ishida T, Mizushima S, Azuma S, Kobayashi N, Tojo T, Suzuki K, Aizawa S, Watanabe T, Mosialos G, Kieff E, Yamamoto T, Inoue J (1996) Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J Biol Chem 271:28745–28748PubMedCrossRefGoogle Scholar
- Munger JS, Huang X, Kawakatsu H, Griffiths MJ, Dalton SL, Wu J, Pittet JF, Kaminski N, Garat C, Matthay MA, Rifkin DB, Sheppard D (1999) The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96:319–328PubMedCrossRefGoogle Scholar
- Pechkovsky DV, Scaffidi AK, Hackett TL, Ballard J, Shaheen F, Thompson PJ, Thannickal VJ, Knight DA (2008) Transforming growth factor beta1 induces alphavbeta3 integrin expression in human lung fibroblasts via a beta3 integrin-, c-Src-, and p38 MAPK-dependent pathway. J Biol Chem 283:12898–12908PubMedCrossRefGoogle Scholar
- Wilkes MC, Mitchell H, Penheiter SG, Dore JJ, Suzuki K, Edens M, Sharma DK, Pagano RE, Leof EB (2005) Transforming growth factor-beta activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2. Cancer Res 65:10431–10440PubMedCrossRefGoogle Scholar
- Xie M, Zhang D, Dyck JR, Li Y, Zhang H, Morishima M, Mann DL, Taffet GE, Baldini A, Khoury DS, Schneider MD (2006) A pivotal role for endogenous TGF-beta-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway. Proc Natl Acad Sci USA 103:17378–17383PubMedCrossRefGoogle Scholar
- Yu N, Kozlowski JM, Park II, Chen L, Zhang Q, Xu D, Doll JA, Crawford SE, Brendler CB, Lee C (2010) Overexpression of transforming growth factor beta1 in malignant prostate cells is partly caused by a runaway of TGF-beta1 auto-induction mediated through a defective recruitment of protein phosphatase 2A by TGF-beta type I receptor. Urology 76:e1518–e1513CrossRefGoogle Scholar