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

View

Book Description

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

View

Book Description

Author: John B. Hudson
Publisher:
ISBN:
Category : Drosophila
Languages : en
Pages : 258

View

Book Description

Author: P. Andrew (Paul Andrew) Chong
Publisher: Library and Archives Canada = Bibliothèque et Archives Canada
ISBN: 9780494028315
Category :
Languages : en
Pages : 304

View

Book Description
Crystal structures of HECT domains from different E3 enzymes suggest that these domains undergo significant conformational change that is important for enzymatic function. To obtain samples of Smurf2 HECT suitable for NMR analysis an iterative screening approach was developed. This approach resulted in significant improvements in NMR spectra and contributes to development of screening methods for NMR. Additionally, these results have increased our understanding of HECT domain dynamics. Transforming Growth Factor beta (TGF-beta) cytokines play central roles in embryogenesis, immunity, and tumour suppression. Signals from these cytokines are propogated through receptors which activate transcription factors called Smads. In addition to binding DNA Smad proteins form regulatory interactions with many cytoplasmic and nuclear proteins. Downregulation of various TGF-beta signalling components is mediated by ubiquitin ligases called Smad Ubiquitin Regulatory Factors (Smurf). The goal of this thesis was to increase understanding of the structural and thermodyanmic basis for Smad and Smurf function. Smurf2 ubiquitinates the TGF-beta receptor complex to target it for degradation. Receptor recognition by Smurf2 occurs through an intermediary protein: Smad7. To probe Smurf2 specificity and recognition of Smad7, the solution structure of a complex between the third WW domain (WW3) of Smurf2 and a peptide from Smad7 containing a PPXY motif was determined. This revealed a novel interaction mode between the WW3 domain and PY motif, which allows Smurf2 to recognize a subset of PY motif containing proteins, including Smad7. This target recognition mode provides a basis for Smurf2 specificity. The Smad2 Mad Homology 2 (MH2) domain binds to many diverse proteins. NMR was used to investigate the structure of one interacting protein, the Smad Binding Domain (SBD) of Smad Anchor for Receptor Activation (SARA). The results indicate that unbound SBD is disordered and forms no stable secondary or tertiary structures. Fluorescence binding studies indicate that no region of SBD dominates the interaction between MH2 and SBD. My results are consistent with a series of hydrophobic patches on the MH2 that are able to recognize disordered regions of proteins. These findings elucidate a mechanism by which a single domain (MH2) can specifically recognize diverse proteins that are unrelated by sequence.

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

View

Book Description
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: Daniel Ethan Nicklas
Publisher:
ISBN: 9781321020564
Category :
Languages : en
Pages :

View

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

View

Book Description
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: Michael Benjamin Major
Publisher:
ISBN:
Category : Cellular signal transduction
Languages : en
Pages : 350

View

Book Description

Author: Jafar Hamzavi Sarkhaei
Publisher:
ISBN:
Category :
Languages : en
Pages : 129

View

Book Description

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

View

Book Description