Characterization of a Novel TGF-[beta] Signal Transduction Pathway PDF Download

Author: Jonathan M. Yingling
Publisher:
ISBN:
Category : Cellular signal transduction
Languages : en
Pages : 382

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Author: Daniel Ethan Nicklas
Publisher:
ISBN: 9781321020564
Category :
Languages : en
Pages :

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Book Description
The transforming growth factor-[beta] (TGF-[beta]) signal transduction pathway controls many cellular processes, including growth, differentiation, apoptosis, and tissue homeostasis. It plays a fundamental role during development and is dysregulated in a number of human diseases, including cancer, vascular disease, and fibrotic conditions, through mutations of its core components. The work presented here investigates signaling in this pathway using mathematical modeling and computational analysis in two primary components. First, it is shown that the new model presented here accurately reproduces experimental behavior in three distinct cell lines, highlighting the role of negative feedback and coupled signaling as key determinants in differentiating the cell-specific dynamic responses to ligand stimulation. The negative feedback loop is further investigated in a variety of distinct motifs for its effect on signaling dynamics, robustness to systemic perturbations, and sensitivity to perturbations of individual processes in the pathway.The second primary component of this work combines methods used in the first component to develop a novel approach to identify potential therapeutic targets and apply it to the TGF-[beta] signaling pathway model. This approach determines therapeutic targets that may restore normal signaling dynamics to the system when its components are mutated while maintaining the dynamics of the normal system substantially unperturbed in the presence of the therapeutic intervention to reduce the potential risk of side effects. This method is then generalized and automated through development of a software package so that it may be readily applied to models of any biochemical system, providing an efficient starting point for further experimental and clinical investigation in the development of novel therapeutics.

Author: Craig H. Bassing
Publisher:
ISBN:
Category : Receptors, Transforming Growth Factor beta
Languages : en
Pages : 408

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Author: Anne Marcoux
Publisher:
ISBN:
Category :
Languages : en
Pages : 160

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"In summary, our results demonstrated that r150 is a negative modulator of TGF-beta responses in keratinocytes, and that it might be a potential marker or molecular target for therapeutic intervention in modulating TGF-beta action in human diseases where TGF-beta plays a pathophysiological role." --

Author:
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Category :
Languages : en
Pages : 0

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The principal goal of this project is to understand the transforming growth factor-Beta (TGF Beta) receptor signal transduction pathways and the molecular mechanism underlying the regulation of the activity of the TOFQ receptor kinases. TGF Beta could suppress the growth of breast cancer cells both in vivo and in vitro (1, 2, 3), and this function requires the expression of functional TGF Beta receptors (2, 3) and downstream signaling molecules (4). The TGF Beta family of cytokines has a wide range of biological functions including tumor suppression, extracellular matrix production, embryonic development, and regulation of differentiation(5). These functions are mediated by three specific surface receptors, Types I, II and III, all of which have been cloned (6, 7, 8, 9). The types I and II receptors for TGF Beta, T BetaRI and T BetaRll, are members of the first known receptor serine/threonine kinase family, and share 40% homology between their kinase domains. T BetaRll contains an extracellular domain which binds TGF beta, a transmembrane domain and a cytoplasmic domain with serine/threonine kinase activity. T BetaRI also has an extracellular domain even though it does not bind TGF Beta when expressed without T BetaRII. The cytoplasmic portion of T BetaRI contains a kinase domain and a membrane proximal region which contains a Oly-Ser rich sequence (OS box) that has been proposed to be important for the activation of T BetaRI (10). Both receptors exist normally as homodimers on the cell surface (11, 12) and their kinase activities are essential for signal transduction (6, 8, 9, 13). Binding of TGF Beta1 to T BetaRII induces the formation of a heteromeric complex of T BetaRI and T BetaRll (6, 8, 9, 13), which results in transphosphorylation of T BetaRI by the constitutively active TJ3Rll.

Author: June LaVerne Traicoff
Publisher:
ISBN:
Category :
Languages : en
Pages : 318

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Author: Frances Weis-Garcia
Publisher:
ISBN:
Category :
Languages : en
Pages : 350

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Author:
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ISBN:
Category :
Languages : en
Pages : 0

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The regulation of the Transforming Growth Factor-Beta (TGF-Beta) signaling pathway and its role in cancer is an area of intense research. We are investigating the regulatory role of casein kinase I (CKI) in the TGF-Beta signaling cascade. We have found that one family member inparticular, CKI epsilon, binds to all Smads and the cytoplasmic domains of the Type I and Type II receptors both in vitro and in vivo. The interaction of CKI epsilon with the Type I and Type II receptors is independent of TGF-beta ligand stimulation. However, the CKI epsilon/Smad interaction is transiently disrupted by TGF-beta stimulation, with complete disassociation by 2 hours. Since CKI epsilon is also a serine/threonine kinase, we examined in vitro phosphorylation of Smads and receptors by CKI epsilon and found that only the receptor activated Smads and the Type II Receptor are phosphorylated by CKI epsilon. In addition, we have mapped the CKIs phosphorylation sites of Smad3 to the MH1 domain and the linker region. Furthermore, in the absence of TGF-beta, transient overexpression of CKI epsilon dramatically reduces basal transcriptional reporter activity, but in the presence of ligand CKI epsilon increases TGF-beta mediated transcription. Finally, CKI epsilon is capable of significantly enhancing the transcriptional activity of smad3. Taken together, these observations provide exciting evidence for a functional role of CKI epsilon in the TGF-beta pathway, a pathway that has been shown to be involved in the development and progression of many different types of cancers.

Author: Rik Derynck
Publisher: CSHL Press
ISBN: 0879697520
Category : Transforming growth factors-beta
Languages : en
Pages : 1108

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Transforming growth factor-[beta] (TGF-[beta]), identified nearly three decades ago, is a secreted polypeptide that functions in critical cell cycle processes, including cellular proliferation, differentiation, and development: It belongs to a large protein family that, in humans, contains 33 members, including activins, inhibins, bone morphogenetic proteins, growth and differentiation factors, and Mullerian inhibiting substance. This volume draws on the world's leading laboratories to comprehensively cover all aspects of the biology of TGF-[beta] and related factors. In addition to providing historical and background information, it describes the cell biology and signaling pathways of TGF-[beta] members in detail, including the roles of TGF-[beta] factors in the development and physiology of humans and model organisms. The last few chapters are devoted to the role of TGF-[beta] members in cancer and other diseases, as well as the possibilities for therapeutics based on knowledge of signaling pathways and macromolecular structures. It serves as a comprehensive reference work for both specialists and researchers less familiar with the field.

Author: Carter Li
Publisher:
ISBN:
Category :
Languages : en
Pages :

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"Transforming Growth Factor [beta] (TGF-[beta]) is a multifunctional growth factor involved in a wide variety of cellular processes. Expressed in a majority of mammalian cells, TGF-[beta] has been shown to play pivotal roles in immunoregulation, cellular homeostasis, apoptosis, and embryonic development. Perturbations in the TGF-[beta] signaling pathway results in extensive vascular, neural, and osteal developmental defects, and massive autoimmune inflammatory responses. TGF-[beta] signals through a pair of transmembrane serine/threonine kinases known as type I (T[beta]RI) and type II TGF-[beta] (T[beta]RII) signaling receptors. The TGF-[beta] ligand binds to T[beta]RII, which transphosphorylates the T[beta]RI receptor, initiating an intracellular phosphorylation cascade where the activated T[beta]RI phosphorylates receptor-regulated Smads (R-Smads) which subsequently bind common-mediator Smads (Co-Smads) forming R-Smad/Co-Smad complexes. The R-Smad/Co-Smad complexes then translocate into the nucleus to regulate gene expression through interactions with transcription factors, co-activators and co-repressors. In addition to the T[beta]RI and T[beta]RII signaling receptors, many cell types express TGF-[beta] co-receptors known as betaglycan and endoglin that bind TGF-[beta] and modulate TGF-[beta] signaling in a cell-specific manner. Our research group has previously identified CD109, a GPI-anchored protein, as a novel TGF-[beta] co-receptor. CD109 binds TGF-[beta] to form a heteromeric complex with the TGF-[beta] signaling receptors and inhibits TGF-[beta] signaling through caveolae-mediated TGF-[beta] receptor internalization and degradation. Furthermore, our group has demonstrated that endogenous CD109 can be released from the cell surface by endogenous PIPLC enzymes and subsequently bind TGF-[beta] with high affinity. Aberrant TGF-[beta] signaling plays a central role in a variety of pathologies. Strategies for regulating aberrant TGF-[beta] action by diminishing TGF-[beta] access to its receptors include development of neutralizing anti-TGF-[beta] antibodies and TGF-[beta] ligand traps. Characterizations of receptor-ligand interactions have demonstrated the potential of receptor ectodomain-based ligand traps to sequester TGF-[beta] and inhibit TGF-[beta] signaling. As CD109 and alpha-2-macroglobulin ([alpha]2m) belong to the same family of thioester containing proteins, I set out to determine if soluble CD109 can act as a TGF-[beta] antagonist. As CD109 and [alpha]2m share similar structural homologies, I set out to determine the putative TGF-[beta] binding domain of CD109. In my findings, I established that soluble CD109 acts as a TGF-[beta] antagonist, by demonstrating the ability of recombinant soluble CD109 protein to bind all three mammalian TGF-[beta] isoforms and negatively modulate TGF-[beta] signaling and TGF-[beta]-induced cellular responses. Furthermore, based on my sequence homology analysis, I predict that the putative TGF-[beta] binding domain of CD109 to encompass amino acids 687-711, which includes a WIW hydrophobic sequence and acidic residues thought to confer TGF-[beta] binding functionality similar to that of T[beta]RII and [alpha]2m. Moreover, I have generated CD109 derived peptides based on the putative binding domain of the CD109 protein and CD109 site-directed mutants to determine the TGF-[beta] binding domain of CD109. My results indicate that peptides derived from the putative binding domain of TGF-[beta] (CD109 amino acid 687-711) can bind all three mammalian TGF-[beta] isoforms, modulate TGF-[beta] signaling and TGF-[beta]-induced cellular responses, and that CD109 site-directed mutants can abrogate CD109 inhibition of TGF-[beta] induced transcriptional activity. Collectively, these findings suggest that soluble CD109 plays an important role in negatively regulating TGF-[beta] signaling and that a putative TGF-[beta] putative binding region of CD109 is at least partially responsible for binding TGF-[beta] and antagonizing TGF-[beta] signaling and responses.In addition to unravelling a potential mechanism by which TGF-[beta] action is regulated by CD109 in vivo, the above findings have important implications in TGF-[beta]-related diseases." --