PHLPPing the Script: Emerging Roles of PHLPP Phosphatases in Cell Signaling

Whereas protein kinases have been successfully targeted for a variety of diseases, protein phosphatases remain an underutilized therapeutic target, in part because of incomplete characterization of their effects on signaling networks. The pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) is a relatively new player in the cell signaling field, and new roles in controlling the balance among cell survival, proliferation, and apoptosis are being increasingly identified. Originally characterized for its tumor-suppressive function in deactivating the prosurvival kinase Akt, PHLPP may have an opposing role in promoting survival, as recent evidence suggests. Additionally, identification of the transcription factor STAT1 as a substrate unveils a role for PHLPP as a critical mediator of transcriptional programs in cancer and the inflammatory response. This review summarizes the current knowledge of PHLPP as both a tumor suppressor and an oncogene and highlights emerging functions in regulating gene expression and the immune system. Understanding the context-dependent functions of PHLPP is essential for appropriate therapeutic intervention.

Dimerization of the Notch Intracellular Domain Results in Distinct Signaling Activity

The Notch signaling pathway is a core component of multicellularity; enabling cells to directly communicate with both their neighbors and the surrounding microenvironment. These signals are translated directly through the Notch proteins, where a fragment of Notch transitions into the nucleus to act as a co-transcription factor, setting into motion a host of physiological responses. Commonly involved in pathways that define a cell’s identity and fate decisions, what appears to be a simplistic pathway instead exists in a state of high-tunability and strict control. Missteps in this pathway are generally embryonically lethal or lead to a suite of congenital disorders and cancers. Therefore, it’s pertinent to understand the mechanisms of Notch that provide its flexibility and pleiotropic outcomes. One such property is its ability to homodimerize on DNA while within its transcriptional activation complex, resulting in an enhanced transcriptional signal of a select pool of Notch target genes. This dissertation reviews the general mechanics behind Notch signaling, discusses how the field of Notch dimerization came to be and where it stands currently, and finally, details my contributions to the understanding of this regulatory mechanism. Despite Notch’s ubiquitous function in metazoan life, there are still many mysteries behind this signaling pathway. The work detailed here describes my time spent as a basic science researcher, where my findings contribute a couple of puzzle pieces to the expansive Notch signaling field.

Developing Curricula for Signaling and Communication Course at Malaysian Railway Academy (MyRa) through Industrial Collaboration Program

This paper presents the propose development of railway signaling and communication curricula at MyRA. The program commenced on 2016 under Industrial Collaboration Program (ICP) with Technology Depository Agency coordination. Thales Portugal provides the laboratory equipment and teaching module. There are three institutions and one railway operator company participate in the program. The program was conducted due to enhanced strong knowledge on railway signaling and communication among the Malaysian academicians. The universities will be able to develop bachelor and diploma railway programs and able to develop laboratories along with hi-tech railway equipment. The ICP railway signaling and communication, consist of four stages, started with basic Train The Trainer (TTT), advanced training, training installation equipment and training simulator. The trainees have gained a lot of experienced and expose to different kind of railway signaling system during the training. At the end of the program, a module of railway signaling and communication course with a lab railway signaling field equipment and CTC simulator were developed.

Nuclear Receptor Signaling: A Home for Nuclear Receptor and Coregulator Signaling Research

The field of nuclear receptor and coregulator signaling has grown into one of the most active and interdisciplinary in eukaryotic biology. Papers in this field are spread widely across a vast number of journals, which complicates the task of investigators in keeping current with the literature in the field. In 2003, we launched Nuclear Receptor Signaling as an Open Access reviews, perspectives and methods journal for the nuclear receptor signaling field. Building on its success and impact on the community, we have added primary research and dataset articles to this list of article categories, and we now announce the re-launch of the journal this month. Here we will summarize the rationale that informed the creation and expansion of the journal, and discuss the possibilities for its future development.

Transcriptomine, a web resource for nuclear receptor signaling transcriptomes

The nuclear receptor (NR) superfamily of ligand-regulated transcription factors directs ligand- and tissue-specific transcriptomes in myriad developmental, metabolic, immunological, and reproductive processes. The NR signaling field has generated a wealth of genome-wide expression data points, but due to deficits in their accessibility, annotation, and integration, the full potential of these studies has not yet been realized. We searched public gene expression databases and MEDLINE for global transcriptomic datasets relevant to NRs, their ligands, and coregulators. We carried out extensive, deep reannotation of the datasets using controlled vocabularies for RNA Source and regulating molecule and resolved disparate gene identifiers to official gene symbols to facilitate comparison of fold changes and their significance across multiple datasets. We assembled these data points into a database, Transcriptomine ( http://www.nursa.org/transcriptomine ), that allows for multiple, menu-driven querying strategies of this transcriptomic “superdataset,” including single and multiple genes, Gene Ontology terms, disease terms, and uploaded custom gene lists. Experimental variables such as regulating molecule, RNA Source, as well as fold-change and P value cutoff values can be modified, and full data records can be either browsed or downloaded for downstream analysis. We demonstrate the utility of Transcriptomine as a hypothesis generation and validation tool using in silico and experimental use cases. Our resource empowers users to instantly and routinely mine the collective biology of millions of previously disparate transcriptomic data points. By incorporating future transcriptome-wide datasets in the NR signaling field, we anticipate Transcriptomine developing into a powerful resource for the NR- and other signal transduction research communities.

Role of transforming growth factor-β in hematologic malignancies

The transforming growth factor-β (TGF-β) signaling pathway is an essential regulator of cellular processes, including proliferation, differentiation, migration, and cell survival. During hematopoiesis, the TGF-β signaling pathway is a potent negative regulator of proliferation while stimulating differentiation and apoptosis when appropriate. In hematologic malignancies, including leukemias, myeloproliferative disorders, lymphomas, and multiple myeloma, resistance to these homeostatic effects of TGF-β develops. Mechanisms for this resistance include mutation or deletion of members of the TGF-β signaling pathway and disruption of the pathway by oncoproteins. These alterations define a tumor suppressor role for the TGF-β pathway in human hematologic malignancies. On the other hand, elevated levels of TGF-β can promote myelofibrosis and the pathogenesis of some hematologic malignancies through their effects on the stroma and immune system. Advances in the TGF-β signaling field should enable targeting of the TGF-β signaling pathway for the treatment of hematologic malignancies.