Signal-Seeker™: Newsletters
Newsletter 5/01/18: Ubiquitin-Proteasome System as a Therapeutic Target: Does Tubulin Care?
Newsletter 3/13/18: Post-translational Modifications of β-catenin and TCF/LEF-1 Regulate Canonical Wnt Signaling
Newsletter 2/20/18: Post-translational Modifications Modulate p53 Tumor Suppressor Functions
Newsletter 10/31/17: Mitochondrial Acetylation: Emerging Concepts and Therapeutic Potential
Newsletter 9/11/17: Microtubule Stabilization by the Post-translational Modification of Acetylation
Newsletter 7/18/17: Post-translational Regulation of Mdm2, an E3 Ubiquitin Ligase for Tumor Suppressor p53
Newsletter 6/13/17: Posttranslational Regulation of Key Transcription Factors in Pluripotent Stem Cells
Newsletter 4/17/17: Post-translational Regulation of Phosphatase and Tensin Homolog
Newsletter 3/21/17: Tau Post-Translational Modifications: Therapeutic Targets for Alzheimer’s Disease
Newsletter 8/03/16: Tyrosine phosphorylation regulates Rho family GTPase activity
Newsletter 7/06/16: PTMs Regulate Cytoskeletal Proteins in Heart Disease
Newsletter 3/08/16: SUMOylation: Functional Regulator of Cytoskeletal Proteins
Newsletter 1/12/16: Vimentin Intermediate Filaments: Regulation by Phosphorylation
Newsletter 8/03/15: Post-translational Modifications - Essential for Protein Regulation
Newsletter 6/01/15: SUMOylation of Mitotic Proteins: Localization and Function
Newsletter 3/09/15: Post-translational Modifications Regulate Ral GTPases
Newsletter 1/23/15: Phosphorylation of RhoA as a Regulator of Signal Transduction
Newsletter 8/04/14: SUMOylation: A Post-translational Modification Targeting Cytoskeletal Proteins
Newsletter 6/05/14: Rho GTPases and Reactive Oxygen Species: Crosstalk and Feedback
Newsletter 4/30/14: Myosin Acetylation Modulates Sarcomere Structure and Function
Newsletter 3/24/14: Lysine Acetylation - Regulator of Diverse Cellular Processes
Newsletter 2/21/14: Integrin-mediated redox control of beta-actin: PDI's Emergence
Newsletter 9/27/13: Neurodegeneration: Rhes, SUMOylation, and Huntington's Disease
Newsletter 9/01/13: Monoubiquitination and Protein Regulation
Newsletter 8/01/13: Ras and Rho Post-translational Modification by Prenylation
Newsletter 6/03/13: Actin Modifications and the Cytoskeleton
Newsletter 3/31/13: Tau PTMs as Therapeutic Targets
Newsletter 10/1/12: Ubiquitination and the Regulation of Rho Family Pathways
Newsletter 6/30/12: Polymodifications of tubulin: Glutamylation and Glycylation
Newsletter 10/1/11: HDAC, Tubulin and Cortactin News
For more specific information about Signal-Seeker™ protein modification detection tools please view our product pages and datasheets.
The ubiquitin-proteasome system (UPS) is a well-characterized protein degradation system in cells whose dysfunction is implicated in many diseases, including neurodegeneration and cancer. Major UPS components are ubiquitin (Ub), Ub ligases, Ub hydrolases (deubiquitinases [DUBs]), and the proteasome. Activation of the UPS begins with attachment of an 8 kDa ubiquitin protein to a target protein by a three step cascade carried out by Ub ligases. Ub itself can be ubiquitinated, leading to poly-ubiquitination, a marker for proteasomal recognition and ultimately degradation (Fig. 1). This is an oversimplification as there are several unique Ub specific chains, as well as mono-ubiquitination, that can regulate multiple facets of a protein’s function. Due to the prevalence of UPS dysfunction in disease and an increased molecular understanding of how ubiquitination degrades protein, interest in targeting the UPS for therapeutic intervention has grown substantially.
Given the proteasome’s role in regulated degradation of poly-ubiquitinated proteins and its dysfunction in cancer, researchers posited that inhibition of the proteasome may be effective for treating cancer cachexia (wasting syndrome). This hypothesis spurred the development of early proteasome inhibitors like MG-132. MG-132’s pharmacological properties precluded its use clinically; however, it launched the...
Also included in this newsletter:
- Signal Seeker™ Kits and Pathway Tools, PTM Antibodies, Beads, and more.
- Related Publications
Protein post-translational modifications (PTMs) such as phosphorylation, acetylation, ubiquitination, and SUMOylation, to name but a few, have evolved to diversify the functions of a single protein and account for the vast increase in proteome complexity and functional diversity. A prime example of the complex and dynamic regulatory power PTMs confer is the Wnt/β-catenin signaling pathway. This pathway regulates cellular proliferation, differentiation, and migration during embryonic development and adult cell homeostasis. In addition, dysregulation of Wnt/β-catenin signaling is implicated in multiple pathological conditions, including carcinogenesis and degenerative diseases. In canonical Wnt-mediated signaling, β-catenin is a key effector and interacts, as a co-transcription factor, with the DNA binding proteins TCF (T cell factor) and LEF-1 (lymphoid enhancer factor 1) to activate the transcription of Wnt/β-catenin target genes including cyclin D1, c-jun, and c-myc. In this newsletter, the functional regulation of β-catenin and TCF/LEF-1 by PTMs is discussed.
Also included in this newsletter:
- Signal Seeker™ Kits and Pathway Tools, PTM Antibodies, Beads, and more.
- Related Publications
The multi-domain, tetrameric p53 protein was discovered in 19791-3, first mistakenly described as an oncogene, before its true function as a powerful tumor suppressor was realized4,5. p53 consists of two N-terminal transactivation domains (TAD1 and TAD2), a proline-rich domain (P-rich), a sequence-specific DNA binding domain (DBD), a linker domain, tetramerization domain (TD), and a lysine-rich, basic C-terminal regulatory (REG) domain5 (Fig. 1). As a transcription factor, p53 can regulate the expression of up to 3000 genes involved in apoptosis, senescence, cell cycle arrest, DNA repair, apoptosis, tumor microenvironment, autophagy, and invasion/metastasis6-8. p53 functionality is spatiotemporally regulated by up to fifty post-translational modifications (PTMs)that occur within multiple domains9-12 (Fig. 1). Here, regulation of p53 by ubiquitination, phosphorylation, and acetylation is discussed.
Also included in this newsletter:
- Signal Seeker™ Kits and Pathway Tools, PTM Antibodies, Beads, and more.
- Related Publications
Acetylation of the epsilon amino group of lysine residues (Nε-acetylation) is an ancient, highly conserved post-translational modification (PTM) that links acetyl coenzyme A (acetyl-CoA) metabolism and cellular signaling. This occurs largely through the opposing activities of lysine acetyl transferases (KATs) and lysine deacetylases (KDACs). In humans, there are 3 major KAT families (GCN5, CBP/p300, and MYST) that all use acetyl-CoA as an essential cofactor to donate an acetyl group to target lysine residues. There are two KDAC families, the zinc-dependent histone deacetylases (HDAC1-11) and the NAD+-dependent sirtuins (SIRT1-7).
It is well documented that acetylation of nuclear histones plays a major role in regulating chromatin compaction and transcriptional activity wherein acetylation favors a more open, transcriptionally active chromatin. Recent proteomic studies have identified over 4,500 non-histone proteins as targets of acetylation, thereby establishing lysine acetylation as a major global PTM. This PTM is present in many, if not all, cellular compartments, including the nucleus, cytoplasm, cell membrane, and mitochondria. Functionally, reversible lysine acetylation has been shown to regulate enzyme activity, protein-protein interactions, and protein localization and stability. In addition, it plays critical regulatory roles in many cellular processes, including gene expression, cellular metabolism, apoptosis, cytoskeleton regulation, and membrane trafficking.
Also included in this newsletter:
- Signal Seeker™ Kits and Pathway Tools, PTM Antibodies, Beads, and more.
- Related Publications
The acetylation post-translational modification (PTM) of tubulin occurs primarily on the lysine at position 40 (Lys40) on the alpha-tubulins of assembled microtubules (MTs). The predominant alpha-tubulin acetyltransferase is TAT1/MEC-17. Deacetylation of acetylated tubulin is mediated by histone deacetylase 6 (HDAC6) or SIRT2, the mammalian homolog of silent information regulator 2/sirtuin type 2. Lys40 has long been considered the sole site of acetylation and while other lysine residues on alpha-tubulin and beta-tubulin are targets for acetylation based on proteomic analyses, functional studies focus on the Lys40 residue within the MT lumen. This newsletter discusses tubulin acetylation, MT stability, and the functionality of acetylated MTs (Fig. 1).
Acetylation is a marker for stabilized, long-lived MTs (defined as MTs resistant to nocodazole- and colchicine-induced depolymerization) with a half-life of hours. Notably, acetylation itself does not cause MT stabilization. However, a recent genetic ablation study strongly supports the conclusion that Lys40 acetylation is required for maintaining long-lived, stable MTs in mammalian cells. Loss of TAT1 resulted in a loss of stable, acetylated MTs that are normally present after nocodazole treatment eliminates dynamic MTs. Conversely, TAT1 overexpression significantly increased the amount of nocodazole-resistant (stable) MTs and fibroblasts lacking the tubulin deacetylase HDAC6 have more nocodazole-resistant MTs. The dogma that acetylation is restricted to stable MTs has been revised in recent years as tubulin acetylation is also found on subpopulations of dynamic MTs (half-life of minutes), such as those found in both young and mature neurons.
Also included in this newsletter:
- Signal Seeker™ Kits and Pathway Tools, PTM Antibodies, Beads, and more.
- Related Publications
The ubiquitin E3 ligase Mdm2 (murine double minute 2; human homolog, Hdm2) is well known for its oncogenic activities and as the master regulator of the powerful tumor suppressor p531,2. Moreover, Mdm2 may function as an oncogenic protein independent of p533. Mdm2 is able to inhibit p53-mediated gene expression through two pathways: inhibition of transcriptional activity by direct binding and ubiquitin-mediated degradation via its E3 ligase activity4; however, the effectiveness of p53 inhibition by direct Mdm2 binding has been questioned5.
Under normal, non-stress conditions, Mdm2 maintains p53 expression and activity at a minimal level to tightly regulate its apoptotic/cell death transcriptional activities. Under conditions of cellular stress, Mdm2-mediated ubiquitination of p53 ceases, allowing p53 to activate transcription of apoptotic genes and those involved in inhibiting cell growth. Much research concludes this is due to Mdm2's auto-inhibition by self-ubiquitination1-3. However, this story appears to be more complex than originally thought5 and involves multiple post-translational modifications (PTMs). Here, we discuss Mdm2's regulation by ubiquitination, SUMOylation, phosphorylation, and acetylation6-8 (Fig. 1).
Also included in this newsletter:
- Signal Seeker™ Kits and Pathway Tools, PTM Antibodies, Beads, and more.
- Related Publications
Pluripotent stem cells (PSCs), characterized by their unlimited self-renewal and differentiation potential, have garnered special attention as therapeutics because of their capacity to differentiate into any cells of the respective adult organism1. There are two general types of PSCs: 1. embryonic stem cells (ESCs) and 2. induced pluripotent stem cells (iPSCs). By definition, PSCs exist in a pluripotent state until differentiation into specialized cells. To maintain stem cells as pluripotent, select transcription factors activate pluripotency-promoting genes and concomitantly suppress differentiation-promoting genes. In turn, the expression level and transactivation ability of these transcription factors are regulated by post-translational modifications (PTMs)2,3. Three key pluripotent transcription factors are Oct4, Sox2, and Nanog3. Their regulation of transcription is complex with each transcription factor able to function independently of the other while also capable of auto-inhibition (e.g., Oct4)4 or forming a heterodimer whereby one factor is regulated by the complex (e.g., Nanog activity is strictly regulated by the Oct4/Sox2 heterodimer)5,6. Understanding the precise regulation of the stability (expression level) and transcriptional activity (DNA-binding affinity) of Oct4, Sox2, and Nanog by PTMs is essential in the study of stem cell homeostasis7.
Click to read more
Also included in this newsletter:
- Signal Seeker™ Kits and Pathway Tools, PTM Antibodies, Beads, and more.
- Related Publications
The phosphatidylinositol (3,4,5)-trisphosphate phosphatase and tensin homolog (PTEN) is a tumor supressor protein discovered 20 years ago by two independent laboratories1. PTEN is also known to regulate diverse cellular functions such as adhesion, migration, proliferation, growth, and survival. PTEN is composed of five domains: an N-terminal phosphatidylinositol (4,5)-bisphosphate (PIP2)-binding domain, a catalytic tensin-type phosphatase domain, a C2 tensin-type domain that binds phospholipids, a C-terminal tail domain, and a PDZ-binding domain (Fig. 1). The role of PTEN as a tumor suppressor is attributed to its lipid phosphatase activity which inhibits the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway integral for cell survival and growth by converting phosphatidylinositol (3,4,5)- trisphosphate (PIP3) into PIP2.
Also included in this newsletter:
- Signal Seeker™ Kits and Pathway Tools, PTM Antibodies, Beads, and more.
- Related Publications
Worldwide, more than 47 million people have been diagnosed with dementia, and the majority of these cases are caused by Alzheimer’s disease (AD); aside from the social burden, this neurodegenerative disease has an associated cost of 1.09% of the global gross domestic product. Severe cognitive impairment that leads to deficits in skilled movements, language, and recognition are pathophysiological hallmarks of AD. On a molecular level, neuropathological hallmarks include formation of beta-amyloid plaques and neurofibrillary tangles (NFTs) comprised of paired helical filaments of hyper-phosphorylated Tau proteins. This newsletter focuses on the mechanistic control of Tau by post-translational modifications (PTMs) and the development of novel AD therapeutics based on regulating the PTM status of Tau.
Also included in this newsletter:
- Signal Seeker™ Kits and Pathway Tools, PTM Antibodies, Beads, and more.
- Related Publications
The Ras GTPase superfamily, which includes Ras, Rho, Rab, Arf, and Ran subfamilies (among others), has been shown to regulate a wide spectrum of cellular functions. GTPases function as molecular switches, cycling between an inactive GDP-bound form and an active GTP-bound form. The Rho GTPase subfamily includes Rho, Rac, and CDC42, and is believed to be involved primarily in the regulation of cytoskeletal organization in response to extracellular growth factors...
Also included in this newsletter:
- Antibodies, G-Switch Activators and Inhibitors, Activation Assays, G-protein Effector Proteins and Kits, NEW Signal Seeker Kits
- Related Publications
Cardiovascular disease accounts for roughly one in every three deaths in the USA with heart disease accounting for the majority of these cases. The pathology of heart disease often involves the death or dysfunction of cardiomyocytes, specialized heart cells that produce the contractile, beating function of the heart. Many different proteins and cell machinery, such as ion channels and pumps, cytoskeletal proteins, and receptors play a significant role in regulating the contractile ability of cardiomyocytes.
Also included in this newsletter:
- New Signal Seeker Kits, Purified Actin Proteins, and Custom Proteins
- Related Publications
The filamentous cytoskeleton is comprised of three distinctive polymer networks: actin filaments, intermediate filaments, and microtubules. Their interplay is responsible for cellular structure, motility, and material transport in order to maintain cellular homeostasis. Also, flexible and rapid cellular responses to external and internal stimuli are possible due...
SUMOylation: Functional Regulator of Cytoskeletal Proteins Click to read more
Also included in this newsletter:
- New Signal Seeker Kits, Antibodies, and Reagents
- Related Publications
Intermediate filaments (IFs) are one of three filament systems comprising the cytoskeleton of metazoan cells. IFs are highly dynamic structures essential for organizing the actin and tubulin filament systems and regulating cell signaling, motility, structure, and adhesion during interphase and mitosis. The function and localization of IFs are regulated ...
Also included in this newsletter:
- New Signal Seeker Kits, Antibodies, and Reagents
- Related Publications
To maintain homeostasis, cells need to respond to changes in the intracellular and extracellular milieu. Some of the changes have to be acted upon quickly to avoid detrimental effects that can lead to cell damage or even death. One way that cells act is through protein post-translational modifications (PTMs) which enable... Click to read more
Also included in this newsletter:
- New PTMtrue Antibodies and Reagents
- Related Publications
Successful execution of mitosis requires exquisite regulation and interplay of a myriad of proteins. Recently, the post-translational modification (PTM) of SUMOylation has emerged as an important functional regulator of mitotic proteins1. SUMO (Small Ubiquitin-like MOdifier) proteins are covalently ligated to ... Click to read more
Also included in this newsletter:
- Available Research Tools and Services
- Related Publications
RalA and RalB GTPases regulate cell motility, morphology, signaling, vesicular trafficking, and endo/exocytosis. The regulation of these functions is critical for the development and spread of cancer1-4, implicating Ral in oncogenesis and metastasis. Both isoforms are integral for Ras-mediated tumorigenesis, metastasis, and invasion... Click to read more
Also included in this newsletter:
- Available Research Tools and Services
- Related Publications
The activity of Rho family GTPases is regulated temporally and spatially by a variety of direct post-translational modifications (PTMs) that include prenylation, ubiquitination, oxidation, nitrosylation, and phosphorylation (Fig. 1). This newsletter focuses on control of RhoA function through phosphorylation. RhoA is a target for a growing number of kinases and as such, phosphorylation is emerging as a central theme in the regulation of this family of proteins2... Click to read more
Also included in this newsletter:
- Available Research Tools and Services
- Related Publications
Upon translation, proteins are trafficked to their proper subcellular location so that they can perform their physiological functions. One mechanism that mediates correct protein localizationand function is post-translational modifications (PTMs). PTMs include protease cleavage, protein folding, and the attachment of molecules such as... Click to read more
Also included in this newsletter:
- Post-translational Modification Research Tools and more.
- Related Publications
- Related Research Tools and Services
Redox agents, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), are key regulators in a variety of signal transduction pathways, including integrin signaling, extracellular matrix adhesion, and inflammation1-3. Rho GTPases are also key regulators of many cellular processes, including cell growth, motility, and adhesion4. While redox agents and Rho GTPases operate through a wide array of... Click to read more
Also included in this newsletter:
- Small GTPase Activation Assays, Activators, and Inhibitors
- Related Publications
- Related Research Tools and Services
The calcium-sensitive sarcomeric complex is the key mechanochemical transducing unit in muscle cells. It contains myosin, actin, tromomyosin, and three different troponins, one of which, troponin C, binds calcium and facilitates myosin binding to F-actin. The functional sarcomere is controlled by... Click to read more
Also included in this newsletter:
- New Acetyl Lysine Antibody (Validated in WB, IP, ChIP, IF)
- Related Publications
- Related Research Tools and Services
Lysine acetylation is a post-translational modification (PTM) crucial for regulating the function and localization of many eukaryotic proteins. This PTM is reversible, regulated by histone deacetylases (HDACs) and histone acetyltransferases (HATs). The first evidence of... Click to read more
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- Related Publications
- Related Research Tools and Services
Cell migration is an integral part of several biological processes including angiogenesis, wound healing, and immune surveillance(1). Integrins are αβ heterodimeric transmembrane receptors that link a cell's dynamic interaction with the extracellular matrix (ECM) to the cytoskeletal rearrangements that are necessary to promote cell motility (See figure 1)... Click to read more
Also included in this newsletter
- Related Publications
- Related Research Tools and Services
The small G-protein Rhes (Ras Homolog Enriched in Striatum) is a 266 amino acid protein found predominantly in striatum, and to a lesser extent, the cerebral cortex (Falk et al., 1999). Recent research has revealed that this GTPase may be key to understanding the paradoxical finding that while many different types of cells throughout the brain and body express wild-type and mutant huntingtin protein (mHTT), striatal neurons (and to a degree, cortical neurons) have a selective vulnerability in Huntington's disease (HD) (Harrison, 2012; Harrison and LaHoste, 2013)... Click to read more
Also included in this newsletter:
- Neurodegeneration Related Publications
- Related Research Tools
Ubiquitination is a post-translational modification (PTM) that involves the covalent attachment of an 8 kDa ubiquitin (Ub) peptide to one or more lysines of a target protein. Modification of a target protein may occur as a single Ub on a single lysine (monoubiquitination), a single Ub on multiple lysines (multiubiquitination) or as ubiquitinated chains in which lysines on the initial protein-conjugated ubiquitin are extended through sequential rounds of ubiquitination (polyubiquitination). The fact that ubiquitin contains seven lysine residues and polyubiquitination has been demonstrated to occur through... Click to read more
Also included in this newsletter:
- Monoubiquitination Related Publications
- Related Research Tools
Ras and Rho GTPases are small G-proteins that cycle between an active GTP-bound form and inactive GDP-bound form. Ras proteins, known for their role in cell proliferation, and Rho proteins, known for their involvement in cell morphology, have common post-translational modifications (PTMs) that have been identified as contributors to oncogenesis1,2. Understanding Ras and Rho PTMs have been of interest for drug discovery groups for many years. Recent studies of signaling pathways mediated by the Ras and Rho PTMs prenylation and/or palmitoylation have identified potential cancer drug targets1,2... Click to read more
Also included in this newsletter:
- Ras and Rho Related Publications
- Ras and Rho Protein Research Tools
Actin, a highly expressed and ubiquitous cytoskeletal protein, is a major substrate for at least 17 post-translational modifications (PTMs)1. PTMs are highly dynamic and often reversible processes where a protein’s functional properties are altered by addition of a chemical group or another protein to its amino acid residues. With roles in cell growth, motility, trafficking, and division, it is imperative to ... Click to read more
Also included in this newsletter:
- Actin Related Publications
- Actin Protein Research Tools
This month, the focus is on Tau PTMs as Therapeutic Targets. This newsletter features the following:
- The Many Faces of Tau in Neurodegeneration
- Tau Related Publications
- Tau Protein Research Tools
Click to download our April Newsletter.
This month, the focus is on Ubiquitination and the Regulation of Rho Family Pathways. This months newsletter features the following:
- Ubiquitination and the Regulation of Rho Family Pathways
- Rho Ubiquitination Publications
- Rho Family Research Tools
Click to download our October Newsletter.
This month, the focus is on Polymodifications of tubulin. This months newsletter features the following:
- Polymodifications of tubulin: Glutamylation and Glycylation
- Tubulin Publication Spotlight
- Tubulin Research Tools
Click to download our July Newsletter.
This month's newsletter focus is on Tubulin. In this issue you will find useful information on the following topics:
- HDAC6: An update on its interaction with tubulin, HSP90 and Cortactin
- Tubulin publications
- Tubulin tools
Click to download our October Newsletter.
