scholarly journals The quest for substrates and binding partners: A critical barrier for understanding the role of ADAMTS proteases in musculoskeletal development and disease

2020 ◽  
Vol 250 (1) ◽  
pp. 8-26
Author(s):  
Brandon Satz‐Jacobowitz ◽  
Dirk Hubmacher
Keyword(s):  
Musculoskeletal Development ◽  
Binding Partners

Role of PRAS40 in Akt and mTOR signaling in health and disease

2012 ◽  
Vol 302 (12) ◽  
pp. E1453-E1460 ◽  
Author(s):  
Claudia Wiza ◽  
Emmani B. M. Nascimento ◽  
D. Margriet Ouwens
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Mtor Signaling ◽  
Cellular Growth ◽  
S6 Kinase ◽  
Binding Partners ◽  
Health And Disease ◽  
Mtor Complex 1 ◽  
Mtor Activity

The proline-rich Akt substrate of 40 kDa (PRAS40) acts at the intersection of the Akt- and mammalian target of rapamycin (mTOR)-mediated signaling pathways. The protein kinase mTOR is the catalytic subunit of two distinct signaling complexes, mTOR complex 1 (mTORC1) and mTORC2, that link energy and nutrients to the regulation of cellular growth and energy metabolism. Activation of mTOR in response to nutrients and growth factors results in the phosphorylation of numerous substrates, including the phosphorylations of S6 kinase by mTORC1 and Akt by mTORC2. Alterations in Akt and mTOR activity have been linked to the progression of multiple diseases such as cancer and type 2 diabetes. Although PRAS40 was first reported as substrate for Akt, investigations toward mTOR-binding partners subsequently identified PRAS40 as both component and substrate of mTORC1. Phosphorylation of PRAS40 by Akt and by mTORC1 itself results in dissociation of PRAS40 from mTORC1 and may relieve an inhibitory constraint on mTORC1 activity. Adding to the complexity is that gene silencing studies indicate that PRAS40 is also necessary for the activity of the mTORC1 complex. This review summarizes the regulation and potential function(s) of PRAS40 in the complex Akt- and mTOR-signaling network in health and disease.

scholarly journals Role of the Ndc1 interaction network in yeast nuclear pore complex assembly and maintenance

2009 ◽  
Vol 185 (3) ◽  
pp. 475-491 ◽  
Author(s):  
Evgeny Onischenko ◽  
Leslie H. Stanton ◽  
Alexis S. Madrid ◽  
Thomas Kieselbach ◽  
Karsten Weis
Keyword(s):  
Nuclear Pore Complex ◽  
Structural Integrity ◽  
Fluorescent Protein ◽  
Interaction Network ◽  
Nucleocytoplasmic Transport ◽  
Nuclear Pore ◽  
Binding Partners ◽  
Interaction Partners ◽  
Redundant Functions

The nuclear pore complex (NPC) mediates all nucleocytoplasmic transport, yet its structure and biogenesis remain poorly understood. In this study, we have functionally characterized interaction partners of the yeast transmembrane nucleoporin Ndc1. Ndc1 forms a distinct complex with the transmembrane proteins Pom152 and Pom34 and two alternative complexes with the soluble nucleoporins Nup53 and Nup59, which in turn bind to Nup170 and Nup157. The transmembrane and soluble Ndc1-binding partners have redundant functions at the NPC, and disruption of both groups of interactions causes defects in Ndc1 targeting and in NPC structure accompanied by significant pore dilation. Using photoconvertible fluorescent protein fusions, we further show that the depletion of Pom34 in cells that lack NUP53 and NUP59 blocks new NPC assembly and leads to the reversible accumulation of newly made nucleoporins in cytoplasmic foci. Therefore, Ndc1 together with its interaction partners are collectively essential for the biosynthesis and structural integrity of yeast NPCs.

Unusual aspects of the polyamine transport system affect the design of strategies for use of polyamine analogues in chemotherapy

2007 ◽  
Vol 35 (2) ◽  
pp. 318-321 ◽  
Author(s):  
J.L.A. Mitchell ◽  
T.K. Thane ◽  
J.M. Sequeira ◽  
R. Thokala
Keyword(s):  
Regulatory Protein ◽  
Feedback System ◽  
Uptake System ◽  
Polyamine Synthesis ◽  
Polyamine Analogues ◽  
Binding Partners ◽  
Polyamine Transport ◽  
Polyamine Uptake ◽  
Tumour Cell Growth

One strategy for inhibiting tumour cell growth is the use of polyamine mimetics to depress endogenous polyamine levels and, ideally, obstruct critical polyamine-requiring reactions. Such polyamine analogues make very unusual drugs, in that extremely high intracellular concentrations are required for growth inhibition or cytotoxicity. Cells exposed to even sub-micromolar concentrations of such analogues can achieve effective intracellular levels because these compounds are incorporated by the very aggressive polyamine uptake system. Once incorporated to these levels, many of these analogues induce the synthesis of a regulatory protein, antizyme, which inhibits both polyamine synthesis and the transporter they used to enter the cell. Thus this feedback system allows steady-state maintenance of effective cellular doses of such analogues. Accordingly, effective cellular levels of polyamine analogues are generally inversely related to their capacity to induce antizyme. Antizyme activity is down-regulated by interaction with several binding partners, most notably antizyme inhibitor, and at least a few tumour tissues exhibit deficiencies in antizyme expression. Our studies explore the role of antizyme induction by several polyamine analogues in their physiological response and the possibility that cell-to-cell differences in antizyme expression may contribute to variable sensitivities to these agents.

scholarly journals Direct role for the Drosophila GIGYF protein in 4EHP-mediated mRNA repression

2019 ◽  
Vol 47 (13) ◽  
pp. 7035-7048 ◽  
Author(s):  
Vincenzo Ruscica ◽  
Praveen Bawankar ◽  
Daniel Peter ◽  
Sigrun Helms ◽  
Cátia Igreja ◽  
...  
Keyword(s):  
Effector Proteins ◽  
Translational Repression ◽  
Direct Role ◽  
Binding Motifs ◽  
Translational Repressor ◽  
Homologous Protein ◽  
Mrna Targets ◽  
Binding Partners ◽  
Specific Mrnas

Abstract The eIF4E-homologous protein (4EHP) is a translational repressor that competes with eIF4E for binding to the 5′-cap structure of specific mRNAs, to which it is recruited by protein factors such as the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins (GIGYF). Several experimental evidences suggest that GIGYF proteins are not merely facilitating 4EHP recruitment to transcripts but are actually required for the repressor activity of the complex. However, the underlying molecular mechanism is unknown. Here, we investigated the role of the uncharacterized Drosophila melanogaster (Dm) GIGYF protein in post-transcriptional mRNA regulation. We show that, when in complex with 4EHP, Dm GIGYF not only elicits translational repression but also promotes target mRNA decay via the recruitment of additional effector proteins. We identified the RNA helicase Me31B/DDX6, the decapping activator HPat and the CCR4–NOT deadenylase complex as binding partners of GIGYF proteins. Recruitment of Me31B and HPat via discrete binding motifs conserved among metazoan GIGYF proteins is required for downregulation of mRNA expression by the 4EHP–GIGYF complex. Our findings are consistent with a model in which GIGYF proteins additionally recruit decapping and deadenylation complexes to 4EHP-containing RNPs to induce translational repression and degradation of mRNA targets.

scholarly journals Post-Translational Modification-Dependent Activity of Matrix Metalloproteinases

2019 ◽  
Vol 20 (12) ◽  
pp. 3077 ◽  
Author(s):  
Elizabeta Madzharova ◽  
Philipp Kastl ◽  
Fabio Sabino ◽  
Ulrich auf dem Keller
Keyword(s):  
Matrix Metalloproteinases ◽  
Transcriptional Control ◽  
Proteolytic Processing ◽  
Post Translational Modification ◽  
Proteolytic Activation ◽  
Control Of Gene Expression ◽  
Post Translational Modifications ◽  
Binding Partners ◽  
Secreted Proteases

Due to their capacity to process different proteins of the extracellular matrix (ECM), matrix metalloproteinases (MMPs) were initially described as a family of secreted proteases, functioning as main ECM regulators. However, through proteolytic processing of various biomolecules, MMPs also modulate intra- and extracellular pathways and networks. Thereby, they are functionally implicated in the regulation of multiple physiological and pathological processes. Consequently, MMP activity is tightly regulated through a combination of epigenetic, transcriptional, and post-transcriptional control of gene expression, proteolytic activation, post-translational modifications (PTMs), and extracellular inhibition. In addition, MMPs, their substrates and ECM binding partners are frequently modified by PTMs, which suggests an important role of PTMs in modulating the pleiotropic activities of these proteases. This review summarizes the recent progress towards understanding the role of PTMs (glycosylation, phosphorylation, glycosaminoglycans) on the activity of several members of the MMP family.

scholarly journals The anterior gradient-2 interactome

2020 ◽  
Vol 318 (1) ◽  
pp. C40-C47 ◽  
Author(s):  
Frederic Delom ◽  
M. Aiman Mohtar ◽  
Ted Hupp ◽  
Delphine Fessart
Keyword(s):  
Disulfide Bonds ◽  
Protein Disulfide Isomerase ◽  
Protein Quality ◽  
Physiological Role ◽  
Disulfide Isomerase ◽  
Cellular Effects ◽  
Binding Partners ◽  
Protein Disulfide ◽  
Biological Outcomes

The anterior gradient-2 (AGR2) is an endoplasmic reticulum (ER)-resident protein belonging to the protein disulfide isomerase family that mediates the formation of disulfide bonds and assists the protein quality control in the ER. In addition to its role in proteostasis, extracellular AGR2 is responsible for various cellular effects in many types of cancer, including cell proliferation, survival, and metastasis. Various OMICs approaches have been used to identify AGR2 binding partners and to investigate the functions of AGR2 in the ER and outside the cell. Emerging data showed that AGR2 exists not only as monomer, but it can also form homodimeric structure and thus interact with different partners, yielding different biological outcomes. In this review, we summarize the AGR2 “interactome” and discuss the pathological and physiological role of such AGR2 interactions.

scholarly journals Nucleophosmin in Its Interaction with Ligands

2020 ◽  
Vol 21 (14) ◽  
pp. 4885
Author(s):  
Ilaria Cela ◽  
Adele Di Matteo ◽  
Luca Federici
Keyword(s):  
Nucleic Acids ◽  
Cellular Response ◽  
Therapeutic Strategy ◽  
Cell Cycle Control ◽  
Dyskeratosis Congenita ◽  
Structural Basis ◽  
Binding Partners ◽  
Nucleolar Organization ◽  
Hematological Cancers

Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both nucleic acids and proteins and plays a role in cell cycle control, centrosome duplication, ribosome maturation and export, as well as the cellular response to a variety of stress stimuli. NPM1 is a hub protein in nucleoli where it contributes to nucleolar organization through heterotypic and homotypic interactions. Furthermore, several alterations, including overexpression, chromosomal translocations and mutations are present in solid and hematological cancers. Recently, novel germline mutations that cause dyskeratosis congenita have also been described. This review focuses on NPM1 interactions and inhibition. Indeed, the list of NPM1 binding partners is ever-growing and, in recent years, many studies contributed to clarifying the structural basis for NPM1 recognition of both nucleic acids and several proteins. Intriguingly, a number of natural and synthetic ligands that interfere with NPM1 interactions have also been reported. The possible role of NPM1 inhibitors in the treatment of multiple cancers and other pathologies is emerging as a new therapeutic strategy.

ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters

Blood ◽  
2011 ◽  
Vol 118 (14) ◽  
pp. 3990-4002 ◽  
Author(s):  
Royston-Luke Huang ◽  
Ziqiang Teo ◽  
Han Chung Chong ◽  
Pengcheng Zhu ◽  
Ming Jie Tan ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Integrin Signaling ◽  
Wild Type ◽  
Integrin Α5β1 ◽  
Vascular Integrity ◽  
Vascular Disruption ◽  
Binding Partners ◽  
Adhesive Proteins

Abstract Vascular disruption induced by interactions between tumor-secreted permeability factors and adhesive proteins on endothelial cells facilitates metastasis. The role of tumor-secreted C-terminal fibrinogen-like domain of angiopoietin-like 4 (cANGPTL4) in vascular leakiness and metastasis is controversial because of the lack of understanding of how cANGPTL4 modulates vascular integrity. Here, we show that cANGPTL4 instigated the disruption of endothelial continuity by directly interacting with 3 novel binding partners, integrin α5β1, VE-cadherin, and claudin-5, in a temporally sequential manner, thus facilitating metastasis. We showed that cANGPTL4 binds and activates integrin α5β1-mediated Rac1/PAK signaling to weaken cell–cell contacts. cANGPTL4 subsequently associated with and declustered VE-cadherin and claudin-5, leading to endothelial disruption. Interfering with the formation of these cANGPTL4 complexes delayed vascular disruption. In vivo vascular permeability and metastatic assays performed using ANGPTL4-knockout and wild-type mice injected with either control or ANGPTL4-knockdown tumors confirmed that cANGPTL4 induced vascular leakiness and facilitated lung metastasis in mice. Thus, our findings elucidate how cANGPTL4 induces endothelial disruption. Our findings have direct implications for targeting cANGPTL4 to treat cancer and other vascular pathologies.

HMGN dynamics and chromatin function

2003 ◽  
Vol 81 (3) ◽  
pp. 113-122 ◽  
Author(s):  
Frédéric Catez ◽  
Jae-Hwan Lim ◽  
Robert Hock ◽  
Yuri V Postnikov ◽  
Michael Bustin
Keyword(s):  
Binding Sites ◽  
Protein Composition ◽  
Nuclear Proteins ◽  
Chromatin Interactions ◽  
Binding Partners ◽  
Nucleosomal Dna ◽  
Transient Interactions ◽  
And Function ◽  
Nucleosome Binding

Recent studies indicate that most nuclear proteins, including histone H1 and HMG are highly mobile and their interaction with chromatin is transient. These findings suggest that the structure of chromatin is dynamic and the protein composition at any particular chromatin site is not fixed. Here we discuss how the dynamic behavior of the nucleosome binding HMGN proteins affects the structure and function of chromatin. The high intranuclear mobility of HMGN insures adequate supply of protein throughout the nucleus and serves to target these proteins to their binding sites. Transient interactions of the proteins with nucleosomes destabilize the higher order chromatin, enhance the access to nucleosomal DNA, and impart flexibility to the chromatin fiber. While roaming the nucleus, the HMGN proteins encounter binding partners and form metastable multiprotein complexes, which modulate their chromatin interactions. Studies with HMGN proteins underscore the important role of protein dynamics in chromatin function.Key words: HMG, nuclear proteins, chromatin, HMGN.

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