TGFβ in Cancer
2008; Cell Press; Volume: 134; Issue: 2 Linguagem: Inglês
10.1016/j.cell.2008.07.001
ISSN1097-4172
Autores Tópico(s)Kruppel-like factors research
ResumoThe transforming growth factor β (TGFβ) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development. The regulatory cytokine TGFβ exerts tumor-suppressive effects that cancer cells must elude for malignant evolution. Yet, paradoxically, TGFβ also modulates processes such as cell invasion, immune regulation, and microenvironment modification that cancer cells may exploit to their advantage. Consequently, the output of a TGFβ response is highly contextual throughout development, across different tissues, and also in cancer. The mechanistic basis and clinical relevance of TGFβ's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway. The transforming growth factor β (TGFβ) signaling pathway is a key player in metazoan biology, and its misregulation can result in tumor development. The regulatory cytokine TGFβ exerts tumor-suppressive effects that cancer cells must elude for malignant evolution. Yet, paradoxically, TGFβ also modulates processes such as cell invasion, immune regulation, and microenvironment modification that cancer cells may exploit to their advantage. Consequently, the output of a TGFβ response is highly contextual throughout development, across different tissues, and also in cancer. The mechanistic basis and clinical relevance of TGFβ's role in cancer is becoming increasingly clear, paving the way for a better understanding of the complexity and therapeutic potential of this pathway. A newcomer in a cytokine family whose members regulate organism development, the regulatory cytokine transforming growth factor β (TGFβ) made its debut with the rise of the vertebrates. TGFβ evolved to regulate the expanding systems of epithelial and neural tissues, the immune system, and wound repair. Tied to these crucial regulatory roles of TGFβ are the serious consequences that result when this signaling pathway malfunctions, namely tumorigenesis. Virtually all human cell types are responsive to TGFβ. TGFβ maintains tissue homeostasis and prevents incipient tumors from progressing down the path to malignancy by regulating not only cellular proliferation, differentiation, survival, and adhesion but also the cellular microenvironment. But as genetically unstable entities, cancer cells have the capacity to avoid or, worse yet, adulterate the suppressive influence of the TGFβ pathway. Pathological forms of TGFβ signaling promote tumor growth and invasion, evasion of immune surveillance, and cancer cell dissemination and metastasis (Figure 1). How can a tumor-suppressor pathway be so radically turned on its head? The answer lies in the points of disruption in TGFβ signaling and the context in which these disruptions occur. Malignant cells can circumvent the suppressive effects of TGFβ either through inactivation of core components of the pathway, such as TGFβ receptors (Figure 2, Path 1), or by downstream alterations that disable just the tumor-suppressive arm of this pathway (Figure 2, Path 2). If the latter mode of circumvention is used, cancer cells can then freely usurp the remaining TGFβ regulatory functions to their advantage, acquiring invasion capabilities, producing autocrine mitogens, or releasing prometastatic cytokines. Thus, beheading of the TGFβ pathway by receptor inactivation can eliminate tumor suppression, whereas amputation of just the growth-inhibitory arm of this pathway not only abolishes growth suppression but also creates added potential for tumor progression. Also relevant to cancer development are the effects of TGFβ on the tumor stroma. TGFβ is a key enforcer of immune tolerance, and tumors that produce high levels of this cytokine may be shielded from immune surveillance. On the other hand, defective TGFβ responsiveness in immune cells can lead to chronic inflammation and the production of a protumorigenic environment. Tumor-derived TGFβ may recruit other stromal cell types such as myofibroblasts (at the invading tumor front) and osteoclasts (in bone metastases), thus furthering tumor spread. A dual role of TGFβ in cancer has long been noted, but its mechanistic basis, operating logic, and clinical relevance have remained elusive. What causes TGFβ signaling to be altered in cancer? What steps in tumor progression may benefit from a faulty TGFβ pathway? When does TGFβ act as a metastatic signal? And, most importantly, how can any of this knowledge be used to treat cancer? A combination of improved model systems, new tools for mechanistic dissection, and diligent mining of clinical data is providing fresh answers. Focusing on this progress, this review pays particular attention to new insights that are relevant to cancer in humans. The human TGFβ family comprises more than 30 factors that can be divided into two distinct branches. Factors such as activin, nodal, lefty, myostatin, and TGFβ are clustered in one family branch, and bone morphogenetic proteins (BMPs), anti-muellerian hormone (AMH, also known as MIS), and various growth and differentiation factors (GDFs) are grouped into the other branch (Derynck and Akhurst, 2007Derynck R. Akhurst R.J. Differentiation plasticity regulated by TGF-beta family proteins in development and disease.Nat. Cell Biol. 2007; 9: 1000-1004Crossref PubMed Scopus (129) Google Scholar, Roberts and Wakefield, 2003Roberts A.B. Wakefield L.M. The two faces of transforming growth factor beta in carcinogenesis.Proc. Natl. Acad. Sci. USA. 2003; 100: 8621-8623Crossref PubMed Scopus (403) Google Scholar, Shi and Massagué, 2003Shi Y. Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell. 2003; 113: 685-700Abstract Full Text Full Text PDF PubMed Scopus (2638) Google Scholar). Activins, nodals, BMPs, AMH/MIS, and GDFs are key regulators of embryonic stem cell differentiation, body axis formation, left-right symmetry, and organogenesis. Roles of these cytokines in the adult organism, besides those mentioned for TGFβ, include regulation of gonadal function by activins and GDF9, inhibition of muscle development by myostatin, and bone growth and repair by BMPs. TGFβ family members display diverse spatial and temporal expression patterns. TGFβ1, for example, is expressed in many cell types, whereas myostatin is expressed in just a few. The spectrum of temporal diversity in TGFβ expression is exemplified by AMH (brief developmental expression) and BMP2 (sustained expression throughout the organism's lifetime). Most members of this cytokine family exist in variant forms (e.g., TGFβ1, β2, and β3). The bioactive cytokine molecule is a dimer composed of a polypeptide chain that is cleaved from a precursor by enzymes such as furins and other convertases. The active TGFβ dimer signals by bringing together two pairs of receptor serine/threonine kinases known as the type I and type II receptors, respectively (Figure 3A). On binding TGFβ, the type II receptors phosphorylate and activate the type I receptors that then propagate the signal by phosphorylating Smad transcription factors. Receptors of the TGFβ branch of the cytokine family phosphorylate Smads 2 and 3, whereas those of the other branch such as BMP receptors phosphorylate Smads 1, 5, and 8 (Figure 3B). Once activated, the receptor substrate Smads (RSmads) shuttle to the nucleus and form a complex with Smad4, a binding partner common to all RSmads (Shi and Massagué, 2003Shi Y. Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell. 2003; 113: 685-700Abstract Full Text Full Text PDF PubMed Scopus (2638) Google Scholar). (A) Ligand traps and coreceptor molecules control the access of TGFβ family ligands to signaling receptors. The ligand assembles a tetrameric complex of receptor serine/threonine kinases types I and II. Receptor-II phosphorylates and activates receptor-I, which then phosphorylates and activates Smad transcription factors (RSmads). Activated RSmads bind Smad4 and further build transcriptional activation and repression complexes to control the expression of hundreds of target genes in a given cell. Mitogen-activated protein kinases (MAPK) and other protein kinases phosphorylate Smads for recognition by ubiquitin ligases and other mechanisms of inactivation. Phosphatases have been identified that reverse these phosphorylation events. (B) An abridged chart of ligand-receptor-coreceptor-Smad relationships in the TGFβ (green) and BMP (blue) branches of the TGFβ family. (C) Distinct combinations of transcription partner cofactors in different contexts (e.g., different cell types or conditions) determine the set of genes targeted by specific activated Smads. Each Smad-cofactor combination coordinately regulates a synexpression group of target genes. Smad signaling serves as a node for integrating regulatory signals that impinge on partner cofactors (e.g., Activator signal in Context 2). (D) Alternative modes of TGFβ signaling include Smad4-independent RSmad signaling (via interactions with TIF1γ, IKKα, p68DROSHA), Smad-independent receptor-I signaling (via small G proteins and MAPK pathways), and direct receptor-II signaling (via Par6, and via LIMK1 in the case of BMPR-II). (E) Core TGFβ pathway components that are affected by mutation (red), overexpression (black), or downregulation (green) in human cancers. Smad proteins possess DNA-binding activity, but the Smad4-RSmad complexes must associate with additional DNA-binding cofactors in order to achieve binding with high affinity and selectivity to specific target genes (Figure 3A). These Smad partners are drawn from various families of transcription factors, such as the forkhead, homeobox, zinc-finger, bHLH, and AP1 families (Feng and Derynck, 2005Feng X.H. Derynck R. Specificity and versatility in tgf-beta signaling through Smads.Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (872) Google Scholar, Massagué et al., 2005Massagué J. Seoane J. Wotton D. Smad transcription factors.Genes Dev. 2005; 19: 2783-2810Crossref PubMed Scopus (1013) Google Scholar). Each Smad4-RSmad-cofactor combination targets a particular set of genes, which is determined by the presence of cognate binding sequence element combinations in the regulatory regions of target genes. Activated Smad complexes additionally recruit transcriptional coactivators, corepressors, and chromatin remodeling factors. Through this combinatorial interaction with different transcription factors, a common TGFβ stimulus can activate or repress hundreds of target genes at once. Built into this mode of TGFβ action are three cardinal features of TGFβ signaling, namely, pleiotropy, coordination, and context dependence. The pleiotropic action of this pathway is based on the large set of transcription factors that can interact with activated Smads to target a large number of functionally diverse genes (Figure 3C). A series of surface hydrophobic patches and pockets on the Smad protein make it particularly suitable for such interactions (Shi and Massagué, 2003Shi Y. Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell. 2003; 113: 685-700Abstract Full Text Full Text PDF PubMed Scopus (2638) Google Scholar). Coordinated regulation of different genes is achieved by their sharing of enhancer element configurations that are recognized by a particular Smad-cofactor complex. Within a TGFβ transcriptional program, this feature defines “synexpression groups” of coordinately regulated genes (Gomis et al., 2006aGomis R.R. Alarcon C. He W. Wang Q. Seoane J. Lash A. Massagué J. A FoxO-Smad synexpression group in human keratinocytes.Proc. Natl. Acad. Sci. USA. 2006; 103: 12747-12752Crossref PubMed Scopus (105) Google Scholar, Niehrs and Pollet, 1999Niehrs C. Pollet N. Synexpression groups in eukaryotes.Nature. 1999; 402: 483-487Crossref PubMed Scopus (222) Google Scholar, Silvestri et al., 2008Silvestri C. Narimatsu M. von Both I. Liu Y. Tan N.B. Izzi L. McCaffery P. Wrana J.L. Attisano L. Genome-wide identification of Smad/Foxh1 targets reveals a role for Foxh1 in retinoic acid regulation and forebrain development.Dev. Cell. 2008; 14: 411-423Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Cells of different types or exposed to different conditions express different repertoires of Smad transcriptional partners, thus linking their TGFβ response to their cellular context. This operating logic allows for the remarkable plasticity of the TGFβ pathway and sets the stage for the severe consequences of its misguided activity in cancer. Variant signaling branches and Smad-independent pathways coexist with the canonical Smad pathway in the response to TGFβ (Figure 3D). Smad4 is essential for many but not all TGFβ-regulated transcriptional responses. Indeed, ablation of SMAD4 in the mammary gland, liver, or pancreas of mice does not derail the development of the targeted organ even though the disruption of TGFβ family receptors does (Bardeesy et al., 2006Bardeesy N. Cheng K.H. Berger J.H. Chu G.C. Pahler J. Olson P. Hezel A.F. Horner J. Lauwers G.Y. Hanahan D. DePinho R.A. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer.Genes Dev. 2006; 20: 3130-3146Crossref PubMed Scopus (196) Google Scholar, Li et al., 2003Li W. Qiao W. Chen L. Xu X. Yang X. Li D. Li C. Brodie S.G. Meguid M.M. Hennighausen L. Deng C.X. Squamous cell carcinoma and mammary abscess formation through squamous metaplasia in Smad4/Dpc4 conditional knockout mice.Development. 2003; 130: 6143-6153Crossref PubMed Scopus (53) Google Scholar, Wang et al., 2005aWang J. Xu N. Feng X. Hou N. Zhang J. Cheng X. Chen Y. Zhang Y. Yang X. Targeted disruption of Smad4 in cardiomyocytes results in cardiac hypertrophy and heart failure.Circ. Res. 2005; 97: 821-828Crossref PubMed Scopus (67) Google Scholar). The existence of RSmad-dependent but Smad4-independent signaling functions is supported by the identification of TIF1γ (transcription intermediate factor 1γ, also known as TRIM33) as a TGFβ signal mediator. TIF1γ interacts with receptor-activated Smad2/3 in competition with Smad4 and participates in TGFβ-induced erythroid differentiation through as yet unknown targets (He et al., 2006He W. Dorn D.C. Erdjument-Bromage H. Tempst P. Moore M.A. Massagué J. Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway.Cell. 2006; 125: 929-941Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). TIF1γ can also act as a Smad4 inhibitor (Dupont et al., 2005Dupont S. Zacchigna L. Cordenonsi M. Soligo S. Adorno M. Rugge M. Piccolo S. Germ-layer specification and control of cell growth by Ectodermin, a Smad4 ubiquitin ligase.Cell. 2005; 121: 87-99Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). Similarly, TGFβ-activated Smad2/3 in mouse keratinocytes binds to IκB kinase α (IKKα) to control expression of the Myc oncogene antagonist MAD1 and keratinocyte differentiation (Descargues et al., 2008Descargues P. Sil A.K. Sano Y. Korchynskyi O. Han G. Owens P. Wang X.J. Karin M. IKKalpha is a critical coregulator of a Smad4-independent TGFbeta-Smad2/3 signaling pathway that controls keratinocyte differentiation.Proc. Natl. Acad. Sci. USA. 2008; 105: 2487-2492Crossref PubMed Scopus (61) Google Scholar). In a remarkable new finding, BMP-activated Smad1 and TGFβ-activated Smad2/3 bind to p68, a component of the microRNA (miRNA) processing complex DROSHA, to target the primary miR-21 transcript (pri-miR-21) for miR-21 production in vascular smooth muscle cells (Davis et al., 2008Davis B.N. Hilyard A.C. Lagna G. Hata A. SMAD proteins control DROSHA-mediated microRNA maturation.Nature. 2008; 454: 56-61Crossref PubMed Scopus (555) Google Scholar). The miRNA miR-21 induces a contractile cell phenotype by downregulating the suppressor PDCD4. Smad-independent modes of TGFβ signaling also include the interaction of the TGFβ receptor complex with the interleukin-1 receptor-effector module called IL1R-TRAF6-TAK1, leading to the activation of JNK and p38 mitogen-activated protein kinase (MAPK) signaling cascades (Lu et al., 2007Lu T. Tian L. Han Y. Vogelbaum M. Stark G.R. Dose-dependent cross-talk between the transforming growth factor-beta and interleukin-1 signaling pathways.Proc. Natl. Acad. Sci. USA. 2007; 104: 4365-4370Crossref PubMed Scopus (56) Google Scholar). Through as yet unknown intermediates, the TGFβ receptor can also engage the Rho-Rock1 signaling module (Bhowmick et al., 2001Bhowmick N.A. Ghiassi M. Bakin A. Aakre M. Lundquist C.A. Engel M.E. Arteaga C.L. Moses H.L. Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism.Mol. Biol. Cell. 2001; 12: 27-36Crossref PubMed Google Scholar), as well as the Cdc42/Rac1-PAK2 complex (Suzuki et al., 2007Suzuki K. Wilkes M.C. Garamszegi N. Edens M. Leof E.B. Transforming growth factor beta signaling via Ras in mesenchymal cells requires p21-activated kinase 2 for extracellular signal-regulated kinase-dependent transcriptional responses.Cancer Res. 2007; 67: 3673-3682Crossref PubMed Scopus (28) Google Scholar). The type II receptors can signal through substrates other than the type I receptors. In epithelial cells, TβR-II phosphorylates Par6, freeing it from a preformed Par6-TβR-I complex. This allows Par6 to trigger the dissolution of tight junctions in the context of epithelial-mesenchymal transitions (Ozdamar et al., 2005Ozdamar B. Bose R. Barrios-Rodiles M. Wang H.R. Zhang Y. Wrana J.L. Regulation of the polarity protein Par6 by TGFbeta receptors controls epithelial cell plasticity.Science. 2005; 307: 1603-1609Crossref PubMed Scopus (407) Google Scholar). The BMP type II receptor can also signal through non-type I receptor substrates: Its unique C-terminal domain modulates the actin cytoskeleton regulatory kinase LIMK1 (Foletta et al., 2003Foletta V.C. Lim M.A. Soosairajah J. Kelly A.P. Stanley E.G. Shannon M. He W. Das S. Massagué J. Bernard O. Direct signaling by the BMP type II receptor via the cytoskeletal regulator LIMK1.J. Cell Biol. 2003; 162: 1089-1098Crossref PubMed Scopus (180) Google Scholar). Many of these noncanonical TGFβ signaling pathways have been investigated in cultured cells, but their relevance to human cancer remains to be established. Under pressure to avoid tumor-suppressive effects, some cancer cells accumulate inactivating mutations in the TGFβ receptors and the Smad proteins (Figure 3E), a pathway for which detailed accounts of the components have been made (Feng and Derynck, 2005Feng X.H. Derynck R. Specificity and versatility in tgf-beta signaling through Smads.Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (872) Google Scholar, Massagué et al., 2005Massagué J. Seoane J. Wotton D. Smad transcription factors.Genes Dev. 2005; 19: 2783-2810Crossref PubMed Scopus (1013) Google Scholar, Shi and Massagué, 2003Shi Y. Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell. 2003; 113: 685-700Abstract Full Text Full Text PDF PubMed Scopus (2638) Google Scholar, Taylor and Wrana, 2008Taylor I.W. Wrana J.L. SnapShot: The TGFbeta pathway interactome.Cell. 2008; 133: 378Abstract Full Text PDF PubMed Scopus (26) Google Scholar). A growing body of evidence also implicates the BMP pathway as a target of disruption in cancer. What follows is an abridged overview highlighting the points of disruptions in these pathways in cancer. Seven type I receptors and five type II receptors paired in different combinations provide the receptor system for the entire TGFβ family (Figure 3B). The cytoplasmic region of these receptors contains a serine/threonine kinase domain. A short segment (the GS domain) just N-terminal to the kinase domain in the type I receptors provides a switch for kinase activation. In the basal state, the GS domain presses against the active center of the kinase, repressing catalytic competence. Ligand-dependent phosphorylation by a type II receptor switches the GS domain from a repressor element into a docking site for substrate Smad proteins. Most members of the TGFβ family share several type I and type II receptors, but TGFβ is an exception. Among the type II receptors, only TβRII can bind to TGFβ. Furthermore, only TβRI can be incorporated into this TβRII-TGFβ complex (Groppe et al., 2008Groppe J. Hinck C.S. Samavarchi-Tehrani P. Zubieta C. Schuermann J.P. Taylor A.B. Schwarz P.M. Wrana J.L. Hinck A.P. Cooperative assembly of TGF-beta superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding.Mol. Cell. 2008; 29: 157-168Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, Shi and Massagué, 2003Shi Y. Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell. 2003; 113: 685-700Abstract Full Text Full Text PDF PubMed Scopus (2638) Google Scholar). What alterations are found at the level of the TGFβ receptors in cancer? Biallelic inactivation of TGFBRII by mutations that truncate the receptor protein or inactivate its kinase domain occur in colon, gastric, biliary, pulmonary, ovarian, esophageal, and head and neck carcinomas (for a detailed listing of known mutations, see Levy and Hill, 2006Levy L. Hill C.S. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer.Cytokine Growth Factor Rev. 2006; 17: 41-58Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). TGFBRII mutations are highly represented in tumors with microsatellite instability, a pathological condition caused by mutations in replication mismatch repair genes. The TGFBRII coding region contains a 10-base polyadenine repeat prone to replication errors that insert or delete one or more adenines. These poly(A) errors remain unrepaired in tumors with microsatellite instability, yielding mutant TGFBRII alleles that encode inactive receptors. This mode of TGFBRII mutation is frequently seen in the inactivation of the second TGFBRII allele. Poly(A) tract TGFBRII mutations accumulate in a majority of sporadic gastrointestinal and biliary carcinomas with microsatellite instability, as well as in lung adenocarcinomas and gliomas. These mutations are also almost universally present in colon cancer patients with inherited mutations in mismatch repair genes. Interestingly, breast tumors and endometrial tumors with microsatellite instability do not accumulate TGFBRII mutations. Biallelic mutations in a poly(A) tract of the activin type II receptor ACVR2 occur in colon tumors with microsatellite instability alongside TGFBRII mutations, suggesting that ACVR2 also plays a role in tumor suppression (Levy and Hill, 2006Levy L. Hill C.S. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer.Cytokine Growth Factor Rev. 2006; 17: 41-58Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). Other mutation types such as frameshift and missense mutations in the TGFBRI coding region are present in subsets of ovarian, esophageal, and head and neck cancers. A common hypomorphic allele, TGFBRI∗6A, is associated with increased risk in certain types of cancers (Kaklamani et al., 2004Kaklamani V. Baddi L. Rosman D. Liu J. Ellis N. Oddoux C. Ostrer H. Chen Y. Ahsan H. Offit K. Pasche B. No major association between TGFBR1∗6A and prostate cancer.BMC Genet. 2004; 5: 28Crossref PubMed Scopus (11) Google Scholar). Receptor alterations can also occur at the epigenetic level. Decreased expression of TGFBRI or TGFBRII occurs frequently in lung, gastric, prostate, and bladder cancers. In gastric cancer, this defect is linked to methylation of the TGFBRI promoter. Finally, germline mutations in the BMP type I receptor BMPRIA occur in a subset of Juvenile Polyposis Syndrome (JPS) cases, an autosomal dominant disorder with predisposition to gastrointestinal polyps and cancer (Levy and Hill, 2006Levy L. Hill C.S. Alterations in components of the TGF-beta superfamily signaling pathways in human cancer.Cytokine Growth Factor Rev. 2006; 17: 41-58Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar, and references therein). Various membrane proteins enhance binding of ligands to the receptors (Figure 3A) (Shi and Massagué, 2003Shi Y. Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus.Cell. 2003; 113: 685-700Abstract Full Text Full Text PDF PubMed Scopus (2638) Google Scholar). The membrane-anchored proteoglycan betaglycan (also called TGFβ type III receptor) binds and presents TGFβ to the TGFβ type II receptor. Betaglycan also mediates the binding of the activin antagonist, inhibin, to activin receptors. The betaglycan-related protein, endoglin (ENG), functions as a BMP9 coreceptor. Inherited mutations in Endoglin cause hemorrhagic telangiectasia syndrome that also includes early-onset JPS (Sweet et al., 2005Sweet K. Willis J. Zhou X.P. Gallione C. Sawada T. Alhopuro P. Khoo S.K. Patocs A. Martin C. Bridgeman S. et al.Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis.JAMA. 2005; 294: 2465-2473Crossref PubMed Scopus (126) Google Scholar). A structurally diverse group of proteins (ligand traps) that “trap” TGFβ family members to limit their access to membrane receptors play critical roles during morphogenesis of the embryo and in the adult (De Robertis and Kuroda, 2004De Robertis E.M. Kuroda H. Dorsal-ventral patterning and neural induction in Xenopus embryos.Annu. Rev. Cell Dev. Biol. 2004; 20: 285-308Crossref PubMed Scopus (349) Google Scholar, Massagué and Chen, 2000Massagué J. Chen Y.G. Controlling TGF-beta signaling.Genes Dev. 2000; 14: 627-644PubMed Google Scholar). For example, the cleaved proregion of the TGFβ precursor called the latency-associated protein (LAP) sequesters TGFβ in a complex that is anchored to the extracellular matrix by the latent TGFβ-binding proteins (LTBP1-4). A different set of proteins (noggin, chordin, gremlin, follistatin, DAN/cerberus, and Bmper) trap BMPs, whereas activins are trapped by follistatins and nodals by DAN/cereberus. Follistatin overexpression is implicated in hepatocarcinogenesis (Rodgarkia-Dara et al., 2006Rodgarkia-Dara C. Vejda S. Erlach N. Losert A. Bursch W. Berger W. Schulte-Hermann R. Grusch M. The activin axis in liver biology and disease.Mutat. Res. 2006; 613: 123-137Crossref PubMed Scopus (44) Google Scholar) and breast cancer bone metastasis (Kang et al., 2003bKang Y. Siegel P.M. Shu W. Drobnjak M. Kakonen S.M. Cordon-Cardo C. Guise T.A. Massagué J. A multigenic program mediating breast cancer metastasis to bone.Cancer Cell. 2003; 3: 537-549Abstract Full Text Full Text PDF PubMed Scopus (1083) Google Scholar). Similarly, Gremlin-1 has been linked to skin basal cell carcinoma and other cancers (Sneddon et al., 2006Sneddon J.B. Zhen H.H. Montgomery K. van de Rijn M. Tward A.D. West R. Gladstone H. Chang H.Y. Morganroth G.S. Oro A.E. Brown P.O. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation.Proc. Natl. Acad. Sci. USA. 2006; 103: 14842-14847Crossref PubMed Scopus (126) Google Scholar). RSmads act as a node for the integration of diverse signaling pathways. In the basal state, RSmads undergo constant nucleocytoplasmic shuttling involving direct interactions with nuclear pore proteins as well as with importins and exportins (Xu, 2006Xu L. Regulation of Smad activities.Biochim. Biophys. Acta. 2006; 1759: 503-513Crossref PubMed Scopus (58) Google Scholar). RSmad phosphorylation by type I receptors occurs at two C-terminal serine residues and triggers the accumulation of RSmads in the nucleus. Cellular stress pathways and receptor tyrosine kinases activate MAPKs, which phosphorylate a linker region that joins the Smad N-terminal and C-terminal domains (MH1 and MH2 domains, respectively). Phosphorylation of these sites in Smad1 enables the binding of the E3 ubiquitin ligase Smurf1, which bars Smad1 interaction with nucleoporins and leads to Smad1 polyubiquitination and degradation (Sapkota et al., 2007Sapkota G. Alarcon C. Spagnoli F.M. Brivanlou A.H. Massagué J. Balancing BMP signaling through integrated inputs into the Smad1 linker.Mol. Cell. 2007; 25: 441-454Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). Linker phosphorylation of Smad2/3 may similarly enhance the binding of other ubiquitin ligases. The protein PPM1A may act as a Smad C-terminal phosphatase, whereas the proteins SCP1–3 function as linker and Smad1 C-terminal phosphatases (Lin et al., 2006Lin X. Duan X. Liang Y.Y. Su Y. Wrighton K.H. Long J. Hu M. Davis C.M. Wang J. Brunicardi F.C. et al.PPM1A functions as a Smad phosphatase to terminate TGFbeta signaling.Cell. 2006; 125: 915-928Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, Sapkota et al., 2006Sapkota G. Knockaert M. Alarcon C. Montalvo E. Brivanlou A.H. Massagué J. Dephosphorylation of the linker regions of Smad1 and Smad2/3 by small C-terminal domain phosphatases has distinct outcomes for bone morphogenetic protein and transforming growth factor-beta pathways.J. Biol. Chem. 2006; 281: 40412-40419Crossref PubMed Scopus (68) Google Scholar). Thus, the opposing actions of TGFβ receptor kinases and Smad phosphatases keep Smad proteins in a rapid activation-deactivation cycle, tying signal flow to receptor activity. Despite their crucial function in connecting signaling pathways, RSmad mutations are infrequent in cancer. Intragenic mutations in SMAD2 occur in a small proportion of colorectal cancers (Sjoblom et al., 2006Sjoblom T. Jones S. Wood L.D. Parsons D.W. Lin J. Barber T.D. Mandelker D. Leary R.J. Ptak J. Silliman N. et al.The consensus coding sequences of human breast and colorectal cancers.Science. 2006; 314: 268-274Crossref PubMed Scopus (1657) Goog
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