Characterization of the Smad Anchor for Receptor Activation in TGFß Signal Transduction PDF Download

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

View

Book Description

Author: Anne Frances Davison
Publisher:
ISBN:
Category :
Languages : en
Pages : 0

View

Book Description
A novel essential component of the Transforming Growth Factor beta (TGFß) signaling pathway that is referred to as SARA, for Smad Anchor for Receptor Activation, has recently been identified (Tsukazaki, T. ' et al.' 1998). Preliminary analysis has revealed that SARA recruits Smad2 to the TGFß receptor complex by controlling its subcellular localization. To further characterize the role of SARA in the signal transduction pathways of the TGFß superfamily, I have undertaken a detailed analysis of this protein. I have shown that SARA is ubiquitously co-expressed with Smad2 in adult human tissues. In addition, dual label immunofluorescence confocal microscopy analysis has demonstrated that SARA localizes specifically to early endosomes, and that PI(3)P participates in mediating this localization. I have also further characterized the association between SARA and the TGFß receptors. I have demonstrated that SARA interacts with specific type I receptors, including the activin receptor-like kinase 1 (ALK1), and the TGFß and activin type I receptors. Moreover, my characterization has revealed that this interaction occurs independent of signaling, and is mediated by the carboxy terminus (amino acids 1000-1323) of SARA. Together, these results lead to a model of SARA functioning as a scaffold for the type I receptor kinase and its substrate, Smad2, in the early endosome.

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: 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: Jolanta Barańska
Publisher: Springer Nature
ISBN: 3030306518
Category : Medical
Languages : en
Pages : 311

View

Book Description
Gliomas, developing in the brain from the transformed glial cells, are a very special kind of tumor, extremely refractory to conventional treatments. Therefore, for the development of new antitumor strategies, a better understanding of molecular mechanisms responsible for their biology, growth and invasion is still needed. This book is a reference on cellular signaling processes regulating gliomas physiology and invasiveness. The work is focused on the mechanism of nucleotide receptor activation by exogenous nucleotides and formation of complex signaling cascades induced by growth factors, cytokines and cannabinoids. The second edition of the book enriched in new chapters provides a framework explaining how signal transduction elements may modulate numerous genetic and epigenetic alterations, describes the role of local microenvironment in cellular growth, progression and invasion and, in the light of extensive new results, presents perspectives concerning potential targets for gliomas therapy.

Author: Ralph A. Bradshaw
Publisher: Academic Press
ISBN: 0123822122
Category : Science
Languages : en
Pages : 459

View

Book Description
A primary component of cell signaling research, this title covers the principal membrane-bound receptor families, including their structural organization. Written and edited by experts in the field, this book provides up-to-date research on transmembrane signaling entities and their initiating responses following extracellular stimulation. - Articles written and edited by experts in the field - Thematic volume covering effectors, cytosolic events, nuclear, and cytoplasmic events - Up-to-date research on signaling systems and mutations in transcription factors that provide new targets for treating disease

Author: Ralph A. Bradshaw
Publisher: Academic Press
ISBN: 0080920918
Category : Science
Languages : en
Pages : 3188

View

Book Description
Handbook of Cell Signaling, Three-Volume Set, 2e, is a comprehensive work covering all aspects of intracellular signal processing, including extra/intracellular membrane receptors, signal transduction, gene expression/translation, and cellular/organotypic signal responses. The second edition is an up-to-date, expanded reference with each section edited by a recognized expert in the field. Tabular and well illustrated, the Handbook will serve as an in-depth reference for this complex and evolving field. Handbook of Cell Signaling, 2/e will appeal to a broad, cross-disciplinary audience interested in the structure, biochemistry, molecular biology and pathology of cellular effectors. - Contains over 350 chapters of comprehensive coverage on cell signaling - Includes discussion on topics from ligand/receptor interactions to organ/organism responses - Provides user-friendly, well-illustrated, reputable content by experts in the field

Author:
Publisher: Academic Press
ISBN: 012385976X
Category : Science
Languages : en
Pages : 269

View

Book Description
This new volume of the renowned serial Current Topics in Developmental Biology covers the important features of growth factors in development. With an international board of authors, this volume will be invaluable for researchers in cell, developmental and molecular biology. - Provides researchers an overview and synthesis of the latest research findings and contemporary thought in the area - This volume provides an up-to-date and timely perspective

Author: George J. Christ
Publisher: Cambridge University Press
ISBN: 0521899494
Category : Medical
Languages : en
Pages : 361

View

Book Description
A state-of-the-art primer on the role of pharmacological sciences in regenerative medicine, for advanced students, postdoctoral fellows, and researchers.