Current Protein and Peptide Science - Volume 19, Issue 4, 2018

Calreticulin (CRT), initially identified as a ubiquitous calcium-binding protein in the endoplasmic reticulum, has emerged as a multifunctional protein with roles in calcium homeostasis, molecular chaperoning and cell adhesion. Emerging evidence suggests its involvement in tumorigenesis facilitating proliferation, migration, and adhesion. CRT translocated to the cell surface (ecto-CRT) serves as a phagocytic signal for immunogenic cell death (ICD) mediated through dendritic cells (DCs) and cytotoxic T-cell activation thereby making tumors susceptible to immunotherapy-based anti-cancer strategies. CRT is now regarded as one of the most potent danger-associated molecular patterns (DAMPs) with the ecto-CRT triggering restoration of homeostasis by immune stimulation. A recently identified novel transacetylase activity of CRT adds a new dimension to its multi-faceted involvement in cancer by virtue of polyphenolic acetates (PA): CRT transacetylase (CRTase) system which results in hyperacetylation of target proteins, thereby mimicking the effects of Histone deacetylase inhibitors (HDACi). Since protein acetylation is one of the crucial post-translational modifications (PTMs) influencing the epigenetic regulation and signal transduction, CRT can be a potential target for developing anticancer therapeutics and preventive strategies by employing pharmacologically compatible semi-synthetic acetyl donors like polyphenolic acetates and other agents.

Natural products serve as a main resource for drug discovery. The ubiquitin-proteasome system (UPS) is one of the primary intracellular protein degradation systems, which is responsible for the degradation of most short-lived, mis-folded and aged proteins. The proteasome is a validated target for cancer treatment, since cancer cells are more reliant on high levels of proteasome activity to maintain the dynamic protein homeostasis required for enhanced metabolism and unrestricted proliferation. Encouraged by success of bortezomib in the treatment of multiple myeloma, several second-generation proteasome inhibitors have been developed based on natural resources, and are being tested in various clinical settings. In this paper, we reviewed the most widely investigated proteasome inhibitors, including their natural product origins, compound-discovery and optimization, as well as their current status in both preclinical and clinical studies.

Cancer is the leading cause of morbidity and mortality worldwide. Therefore, the search for new and less aggressive treatments is currently the focus of the anticancer research. An attractive alternative for this purpose is the use of bioactive peptides from plants. Plants live everywhere on Earth, both on land and in water, and they are a major source of diverse molecules with pharmacological potential as antioxidant peptides. Hence, this review focuses on the importance of the antioxidant activity of terrestrial and aquatic plant peptides against cancer throughout several mechanisms. The influence of the antioxidant activity of peptides by different factors such as molecular weight and amino acid composition as a crucial factor for anticancer activity is also revised. Furthermore, the relation of antioxidant activity with anticancer property as well as safety and legal aspects of protein hydrolysates and bioactive peptides for their use in cancer treatments is discussed.

The epidermal growth factor receptor (EGFR) belongs to ErbB family of tyrosine kinases, which plays an important role in the regulation of cell proliferation, survival, differentiation, and metastasis. In addition, tumors develop resistance to EGFR inhibitors due to the presence or development of point mutations in the tyrosine kinase domain of the receptor. There is an urgent need to develop new anti-EGFR agents with strong therapeutic activities. As the majority of anticancer drugs are of natural origin, natural products are a valuable source for the identification and development of novel treatment options for cancer. To identify promising new anti-tumor agents that act on the EGFR, numerous studies have been carried out and some investigators found natural products that could effectively inhibit the EGFR. This review summarizes the latest developments related to anti- EGFR agents derived from natural compounds and traditional Chinese medicine (TCM).

Plant architecture, the three-dimensional organization of the plant body, includes the branching pattern and the size, shape, and position of organs. Plant architecture is genetically controlled and is influenced by environmental conditions. The regulations occur at most of the stages from the first division of the fertilized eggs to the final establishment of plant architecture. Among the various endogenous regulators, protein kinases and their associated signaling pathways have been shown to play important roles in regulating the process of plant architecture establishment. In this review, we summarize recent progress in the understanding of the mechanisms by which plant architecture formation is regulated by protein kinases, especially mitogen-activated protein kinase (MAPK).

Seed germination and plant growth are key stages in the plant life cycle and they are affected by abiotic stresses. Protein phosphorylation is commonly involved in key regulatory process, which mediates plant growth/development and stress responses. In plant, phosphoproteins play roles in stress responses and provide basic backbone in complex signaling networks. The mechanism of plant responses to abiotic stresses has been uncovered through study of protein phosphorylation. Recently, new methods for enrichment of phosphopeptides and phosphoproteins have been developed. Phosphoproteomic techniques are widely applied to studies of seed germination and plant growth. The signaling networks of phytohormones have been explored using the phosphoproteomic approach. In this review, the enrichment methods of phosphopeptides and phosphoproteins are summarized for phosphoproteomics. The roles of protein kinases and phosphatases in plant are described. The significant achievements of phosphoproteomics in the areas of seed germination and plant growth under abiotic stresses are reviewed. Applications of phosphoproteomics are valuable resources to uncover functional proteins regulating plant growth and stress responses.

Abiotic stresses like salinity, drought, heat, metal ions, radiation and oxidative stress, and especially their combinations, are major limiting factors for growth and productivity of the crops. Various molecular and biochemical processes governing the plant responses to abiotic stresses have often been investigated and hold the key for producing high-yielding and abiotic stress-tolerant crops. Plant responses to abiotic stresses are dynamic and intricate, and vary with type, level, and duration of the stress involved, as well as on the type of tissue under stress. However, one biochemical indicator common to all stresses is definite and controlled protein phosphorylation which is generally transmitted by highly complex protein kinase cascades. In recent years, using different biochemical as well as computational tools, many of such phosphoproteins are identified and characterized with respect to abiotic stresses. Subsequently, an upsurge has been witnessed in recent times for phosphoproteomics repositories or databases. The use of this crucial knowledge about such proteins and their phosphorylation sites is one of the promising ways for crop engineering against abiotic stress. Several reports have described abiotic stress-induced transcriptome, proteome and phosphoproteome changes in plants subjected to these stress factors. However, the investigations to assess precise phosphoproteomics deviations in response to environmental stresses and their implementation for crop improvement are limited. The present review summarizes and discusses the recent developments in deciphering abiotic stress induced changes in plant phosphoproteome besides development of phosphoproteomics tools and their repositories. A critical assessment of targeting phosphoproteins for crop improvement and phosphoproteomics mediated enhanced abiotic stress tolerance in transgenic plants has been presented.