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First published online August 16, 2005
doi: 10.1242/10.1242/jcs.02554

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Non-Smad TGF-ß signals

Ludwig Institute for Cancer Research, Biomedical Center, Uppsala University, Box 595, SE 751 24 Uppsala, Sweden

View larger version (14K): [in a new window]   Fig. 1. Non-Smad signalling. The canonical Smad pathway starting from the ligand-receptor complex and ending in the nucleus is illustrated by thick black arrows. Non-Smad signalling mechanisms are shown by thin blue arrows. The receptor complex activates (by interaction and/or phosphorylation) protein X, which then modulates the activity of the Smad (pathway 1). The phosphorylated Smad activates (by interaction) protein Y, which then transmits further signals into the cell (pathway 2). The receptor complex activates (by interaction and/or phosphorylation) protein Z, which then transmits signals without direct crosstalk with the Smad (pathway 3). Proteins X, Y and Z can be enzymes (e.g. protein or lipid kinases) or adaptor proteins.

View larger version (27K): [in a new window]   Fig. 2. (A) The canonical Smad pathway. TGF-ß bound to the two receptor serine/threonine kinases (type II, light green; type I, blue) initiates signalling by trans-phosphorylation of the type I receptor juxtamembrane domain (red arrow). Signalling ensues with R-Smad phosphorylation (Smad with black dot), oligomerization of R-Smad with Smad4, nuclear translocation and formation of complexes between transcription factors (TF) and co-activators/co-repressors (co) on chromatin. This leads to positive or negative regulation of mRNA synthesis (grey arrow). (B) The inhibitory I-Smad, together with the E3 ligase Smurf, exit the nucleus in response to the incoming TGF-ß signal and bind the receptor complex, leading to shut-down of R-Smad phosphorylation and receptor downregulation.

View larger version (29K): [in a new window]   Fig. 3. (A) Smads in apoptosis. TGF-ß receptors induce through Smads the expression of DAPK, SHIP and TIEG pro-apoptotic genes. Smads also bind and inactivate the survival kinase Akt, thus promoting apoptosis. TGF-ß can also mobilize the mitochondrial serpin ARTS to the nucleus, which blocks XIAPs, the inhibitors of caspases, thus leading to apoptotic events. (B) The TAK1 pathway leading to apoptosis. The TGF-ß type I receptor binds Smad7, the type II receptor binds the pro-apoptotic protein Daxx, whereas BMP receptors bind XIAP and its interacting partners, TAB and TAK1. Both TGF-ß and BMP receptors activate TAK1, leading to MKK3, MKK4 or MKK7 activation. This activates JNK or p38, both of which lead to apoptosis of various cell types. In the Daxx pathway, HIPK2 phosphorylates Daxx (curved arrow), which then activates MKK4 and MKK7.

View larger version (26K): [in a new window]   Fig. 4. Regulation of the actin cytoskeleton and the EMT response. (A) TGF-ß induces Smads, which regulate genes such as that encoding Snail, the transcriptional repressor of E-cadherin gene expression that leads to the dissolution of adherens junctions. Alternatively, the receptors constitutively associate with occludin and the polarity protein Par6. Upon ligand stimulation, the type II receptor phosphorylates Par6 directly. This then recruits the ubiquitin ligase Smurf1, which ubiquitylates and degrades RhoA, thus leading to dissolution of tight junctions. The combined outcome of the two pathways cooperatively promotes EMT. (B) TGF-ß activates Rho GTPases, which activate ROCK, followed by phosphorylation and activation of Limk2 and subsequent phosphorylation and inhibition of cofilin. Cofilin is an actin-binding protein that leads to actin depolymerization. BMP receptors bind directly to Limk1 and activate it, leading to inhibition of cofilin. The net effect of both pathways is a shift towards actin polymerization (thick arrow).

View larger version (22K): [in a new window]   Fig. 5. Epithelial growth suppression induced by TGF-ß. The TGF-ß receptors activate Smads, which induce p21 expression in cooperation with the transcription factors FoxO, p53 and Sp1. The Smad pathway also induces transcription of p15 or p57 and represses expression of Myc and Id genes. The net result of all these transcriptional events is the arrest of the cell cycle in early G1 phase. Smads can also activate PKA, which leads to Sp1 phosphorylation and induction of p21 expression. The TGF-ß receptor also binds the regulatory subunit Ba of PP2A phosphatase, leading to inactivation of p70 S6K kinase, thus indirectly inhibiting cell-cycle progression.

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