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Structure and dynamics of intrinsically disordered regions of MAPK signalling proteins / Structure et dynamique des régions intrinsèquement désordonnées des MAPKKragelj, Jaka 11 December 2014 (has links)
Les voies de transduction du signal cellulaire permettent aux cellules de répondre aux signaux de l'environnement et de les traiter. Les voies de transduction de kinases MAP (MAPK) sont bien conservées dans toutes les cellules eucaryotes et sont impliquées dans la régulation de nombreux processus cellulaires importants. Les régions intrinsèquement désordonnées (RID), présentes dans de nombreuses MAPK, n'étaient pas encore structurellement caractérisées. Les RID de MAPK sont particulièrement importantes car elles contiennent des motifs de liaison qui contrôlent les interactions entre les protéines MAPK elles-mêmes et aussi entre les protéines MAPK et d'autres protéines contenant les mêmes motifs. La résonance magnétique nucléaire (RMN) en combinaison avec d'autres techniques biophysiques a été utilisée pour étudier les RID de kinase des voies de transduction du signal MAPK. La spectroscopie RMN est bien adaptée pour l'étude des protéines intrinsèquement désordonnées à l'échelle atomique. Les déplacements chimiques et couplages dipolaires résiduels peuvent être utilisés conjointement avec des méthodes de sélection d'ensemble pour étudier la structure résiduelle dans les RID. La relaxation de spin nucléaire nous renseigne sur les mouvements rapides. Des titrations par RMN et des techniques de spectroscopie d'échange peuvent être utilisées pour surveiller la cinétique d'interactions protéine-protéine. Cette étude contribuera à la compréhension du rôle des RID dans les voies de transduction du signal cellulaire. / Protein signal transduction pathways allow cells respond to and process signals from the environment. A group of such pathways, called mitogen-activated protein kinase (MAPK) signal transduction pathways, is well conserved in all eukaryotic cells and is involved in regulating many important cell processes. Long intrinsically disordered region (IDRs), present in many MAPKs, have remained structurally uncharacterised. The IDRs of MAPKs are especially important as they contain docking-site motifs which control the interactions between MAPK proteins themselves and also between MAPKs and other interacting proteins containing the same motifs. Nuclear magnetic resonance (NMR) spectroscopy in combination with other biophysical techniques was used to study IDRs of MAPKs. NMR spectroscopy is well suited for studying intrinsically disordered proteins (IDPs) at atomic-level resolution. NMR observables, such as for example chemical shifts and residual dipolar couplings, can be used together with ensemble selection methods to study residual structure in IDRs. Nuclear spin relaxation informs us about fast pico-nanosecond motions. NMR titrations and exchange spectroscopy techniques can be used to monitor kinetics of protein-protein interactions. The mechanistic insight into function of IDRs and motifs will contribute to understanding of how signal transduction pathways work.
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Identification of downstream targets of ALK signaling in Drosophila melanogaster /Varshney, Gaurav, January 2008 (has links)
Diss. (sammanfattning) Umeå : Umeå universitet, 2008. / Härtill 5 uppsatser.
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Regulation and Function of Stress-Activated Protein Kinase Signal Transduction Pathways: A DissertationBrancho, Deborah Marie 14 January 2005 (has links)
The c-Jun NH2-terminal kinase (JNK) group and the p38 group of mitogen-activated protein kinases (MAPK) are stress-activated protein kinases that regulate cell proliferation, differentiation, development, and apoptosis. These protein kinases are involved in a signal transduction cascade that includes a MAP kinase (MAPK), a MAP kinase kinase (MAP2K), and a MAP kinase kinase kinase (MAP3K). MAPK are phosphorylated and activated by the MAP2K, which are phosphorylated and activated by various MAP3K.
The work presented in this dissertation focuses on understanding the regulation and function of the JNK and p38 MAPK pathways. Two different strategies were utilized. First, I used molecular and biochemical techniques to examine how MAP2K and MAP3K mediate signaling specificity and to define their role in the MAPK pathway. Second, I used gene targeted disruption studies to determine the in vivo role ofMAP2K and MAP3K in MAPK activation. I specifically used these approaches to examine: (1) docking interactions between p38 MAPK and MAP2K [MKK3 and MKK6 (Chapter II)]; (2) the differential activation of p38 MAPK by MAP2K [MKK3, MKK4, and MKK6 (Chapter III)]; and (3) the selective involvement of the mixed lineage kinase (MLK) group of MAP3K in JNK and p38 MAPK activation (Chapter IV and Appendix). In addition, I analyzed the role of the MKK3 and MKK6 MAP2K in cell proliferation and the role of the MLK MAP3K in adipocyte differentiation (Chapter III and Chapter IV). Together, these data provide insight into the regulation and function of the stress-activated MAPK signal transduction pathways.
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The Role of RIP1 in the TNFR1 Signal Transduction Pathway: a DissertationLee, Thomas H. 24 September 2004 (has links)
The cytokine tumor necrosis factor α (TNFα) stimulates the NF-кB, SAPK/JNK, and p38 mitogen-activated protein (MAP) kinase pathways by recruiting Rip1 and Traf2 proteins to the tumor necrosis factor receptor 1 (TNFR1). Genetic studies have revealed that Rip1 links the TNFR1 to the IкB kinase (IKK) complex, whereas Traf2 couples the TNFR1 to the SAPK/JNK cascade. We found TNFα-induced p38 MAP kinase activation and interleukin-6 (IL-6) production is impaired in rip1-/- murine embryonic fibroblasts (MEF) but unaffected in traj2-/- MEF, demonstrating that Rip1 is also a specific mediator of the p38 MAP kinase response to TNFα. Moreover, we demonstrate that endogenous Rip1 associates with the MAP3K, Mekk3 in response to TNFα and that TNFα-induced p38 MAP kinase activation is impaired in mekk3-/- cells, indicating that Rip1 may mediate the p38 MAP kinase response to TNFα by recruiting Mekk3.
We also demonstrate that Rip1 is phosphorylated and ubiquitinated in response to Tnfα and that Rip1 phosphorylation is not required for ubiquitination of Rip1. Furthermore, TNFα-induced ubiquitination of Rip1 is impaired in Traf2-/- cells, suggesting that Traf2 is the E3 ubiquitin ligase responsible for the TNFα-dependent ubiquitination of Rip1. Finally, recruitment of the ubiquitinated Tak1 complex is dependent on the presence of Rip1, suggesting that Rip1 ubiquitination rather than its phosphorylation is critical in TNFR1 signaling.
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Jun Kinases in Hematopoiesis, and Vascular Development and Function: A DissertationRamo, Kasmir 06 July 2015 (has links)
Arterial occlusive diseases are major causes of morbidity and mortality in industrialized countries and represent a huge economic burden. The extent of the native collateral circulation is an important determinant of blood perfusion restoration and therefore the severity of tissue damage and functional impairment that ensues following arterial occlusion. Understanding the mechanisms responsible for collateral artery development may provide avenues for therapeutic intervention. Here, we identify a critical requirement for mixed lineage kinase (MLK) – cJun-NH2-terminal kinase (JNK) signaling in vascular morphogenesis and native collateral artery development. We demonstrate that Mlk2-/-Mlk3-/- mice or mice with compound JNK-deficiency in the vascular endothelium display abnormal collateral arteries, which are unable to restore blood perfusion following arterial occlusion, leading to severe tissue necrosis in animal models of femoral and coronary artery occlusion. Employing constitutive and inducible conditional deletion strategies, we demonstrate that endothelial JNK acts during the embryonic development of collateral arteries to ensure proper patterning and maturation, but is dispensable for angiogenic and arteriogenic responses in adult mice. During developmental vascular morphogenesis, MLK – JNK signaling is required for suppression of excessive sprouting angiogenesis likely via JNK-dependent regulation of Dll4 expression and Notch signaling. This function of JNK may underlie its critical requirement for native collateral artery formation. Thus, this study introduces MLK – JNK signaling as a major regulator of vascular development.
In contrast, we find that JNK in hematopoietic cells, which are thought to share a common mesodermally-derived precursor with endothelial cells, is cellautonomously dispensable for normal hematopoietic development and hematopoietic stem cell self-renewal, illustrating the highly context dependent function of JNK.
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Tumor suppressive effects of the Beta-2 adrenergic receptor and the small GTPase RhoBCarie, Adam E. January 2008 (has links)
Dissertation (Ph.D.)--University of South Florida, 2008. / Title from PDF of title page. Document formatted into pages; contains 201 pages. Includes vita. Includes bibliographical references.
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An investigation into dynamic and functional properties of prokaryotic signalling networksKothamachu, Varun Bhaskar January 2016 (has links)
In this thesis, I investigate dynamic and computational properties of prokaryotic signalling architectures commonly known as the Two Component Signalling networks and phosphorelays. The aim of this study is to understand the information processing capabilities of different prokaryotic signalling architectures by examining the dynamics they exhibit. I present original investigations into the dynamics of different phosphorelay architectures and identify network architectures that include a commonly found four step phosphorelay architecture with a capacity for tuning its steady state output to implement different signal-response behaviours viz. sigmoidal and hyperbolic response. Biologically, this tuning can be implemented through physiological processes like regulating total protein concentrations (e.g. via transcriptional regulation or feedback), altering reaction rate constants through binding of auxiliary proteins on relay components, or by regulating bi-functional activity in relays which are mediated by bifunctional histidine kinases. This study explores the importance of different biochemical arrangements of signalling networks and their corresponding response dynamics. Following investigations into the significance of various biochemical reactions and topological variants of a four step relay architecture, I explore the effects of having different types of proteins in signalling networks. I show how multi-domain proteins in a phosphorelay architecture with multiple phosphotransfer steps occurring on the same protein can exhibit multistability through a combination of double negative and positive feedback loops. I derive a minimal multistable (core) architecture and show how component sharing amongst networks containing this multistable core can implement computational logic (like AND, OR and ADDER functions) that allows cells to integrate multiple inputs and compute an appropriate response. I examine the genomic distribution of single and multi domain kinases and annotate their partner response regulator proteins across prokaryotic genomes to find the biological significance of dynamics that these networks embed and the processes they regulate in a cell. I extract data from a prokaryotic two component protein database and take a sequence based functional annotation approach to identify the process, function and localisation of different response regulators as signalling partners in these networks. In summary, work presented in this thesis explores the dynamic and computational properties of different prokaryotic signalling networks and uses them to draw an insight into the biological significance of multidomain sensor kinases in living cells. The thesis concludes with a discussion on how this understanding of the dynamic and computational properties of prokaryotic signalling networks can be used to design synthetic circuits involving different proteins comprising two component and phosphorelay architectures.
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Role of Map4k4 in Skeletal Muscle Differentiation: A DissertationWang, Mengxi 01 May 2013 (has links)
Skeletal muscle is a complicated and heterogeneous striated muscle tissue that serves critical mechanical and metabolic functions in the organism. The process of generating skeletal muscle, myogenesis, is elaborately coordinated by members of the protein kinase family, which transmit diverse signals initiated by extracellular stimuli to myogenic transcriptional hierarchy in muscle cells. Mitogen-activated protein kinases (MAPKs) including p38 MAPK, c-Jun N terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) are components of serine/threonine protein kinase cascades that play important roles in skeletal muscle differentiation. The exploration of MAPK upstream kinases identified mitogen activated protein kinase kinase kinase kinase 4 (MAP4K4), a serine/threonine protein kinase that modulates p38 MAPK, JNK and ERK activities in multiple cell lines. Our lab further discovered that Map4k4 regulates peroxisome proliferator-activated receptor γ (PPARγ) translation in cultured adipocytes through inactivating mammalian target of rapamycin (mTOR), which controls skeletal muscle differentiation and hypotrophy in kinase-dependent and -independent manners. These findings suggest potential involvement of Map4k4 in skeletal myogenesis.
Therefore, for the first part of my thesis, I characterize the role of Map4k4 in skeletal muscle differentiation in cultured muscle cells. Here I show that Map4k4 functions as a myogenic suppressor mainly at the early stage of skeletal myogenesis with a moderate effect on myoblast fusion during late-stage muscle differentiation. In agreement, Map4k4 expression and protein kinase activity are declined with myogenic differentiation. The inhibitory effect of Map4k4 on skeletal myogenesis requires its kinase activity. Surprisingly, none of the identified Map4k4 downstream effectors including p38 MAPK, JNK and ERK is involved in the Map4k4-mediated myogenic differentiation. Instead, expression of myogenic regulatory factor Myf5, a positive mediator of skeletal muscle differentiation is transiently regulated by Map4k4 to partially control skeletal myogenesis. Mechanisms by which Map4k4 modulates Myf5 amount have yet to be determined.
In the second part of my thesis, I assess the relationship between Map4k4 and IGF-mediated signaling pathways. Although siRNA-mediated silencing of Map4k4 results in markedly enhanced myotube formation that is identical to the IGF-induced muscle hypertrophic phenotype, and Map4k4 regulates IGF/Akt signaling downstream effector mTOR in cultured adipocytes, Map4k4 appears not to be involved in the IGF-mediated ERK1/2 signaling axis and the IGF-mediated Akt signaling axis in C2C12 myoblasts. Furthermore, Map4k4 does not affect endogenous Akt signaling or mTOR activity during C2C12 myogenic differentiation.
The results presented here not only identify Map4k4 as a novel suppressor of skeletal muscle differentiation, but also add to our knowledge of Map4k4 action on multiple signaling pathways in muscle cells during skeletal myogenesis. The effects that Map4k4 exerts on myoblast differentiation, fusion and Myf5 expression implicate Map4k4 as a potential drug target for muscle mass growth, skeletal muscle regeneration and muscular dystrophy.
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Fibroblast growth factor receptor 1 promotes proliferation and survival via activation of the mitogen-activated protein kinase pathway in bladder cancerTomlinson, D.C., Lamont, F.R., Shnyder, Steven, Knowles, M.A. January 2009 (has links)
No / Fibroblast growth factor receptors (FGFR) play key roles in proliferation, differentiation, and tumorigenesis. Many urothelial carcinomas contain activating point mutations or increased expression of FGFR3. However, little is known about the role of other FGFRs. We examined FGFR expression in telomerase-immortalized normal human urothelial cells, urothelial carcinoma cell lines, and tumor samples and showed that FGFR1 expression is increased in a high proportion of cell lines and tumors independent of stage and grade. To determine the role of FGFR1 in low-stage bladder cancer, we overexpressed FGFR1 in telomerase-immortalized normal human urothelial cells and examined changes in proliferation and cell survival in response to FGF2. FGFR1 stimulation increased proliferation and reduced apoptosis. To elucidate the mechanistic basis for these alterations, we examined the signaling cascades activated by FGFR1. FRS2alpha and PLCgamma were activated in response to FGF2, leading to activation of the mitogen-activated protein kinase pathway. The level of mitogen-activated protein kinase activation correlated with the level of cyclin D1, MCL1, and phospho-BAD, which also correlated with FGFR-induced proliferation and survival. Knockdown of FGFR1 in urothelial carcinoma cell lines revealed differential FGFR1 dependence. JMSU1 cells were dependent on FGFR1 expression for survival but three other cell lines were not. Two cell lines (JMSU1 and UMUC3) were dependent on FGFR1 for growth in soft agar. Only one of the cell lines tested (UMUC3) was frankly tumorigenic; here, FGFR1 knockdown inhibited tumor growth. Our results indicate that FGFR1 has significant effects on urothelial cell phenotype and may represent a useful therapeutic target in some cases of urothelial carcinoma.
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