JAKs in pathology: role of Janus kinases in hematopoietic malignancies and immunodeficiencies

The four mammalian Janus kinase (JAK) family members, JAK1, JAK2, JAK3 and TYK2, are non-receptor protein tyrosine kinases (PTKs) that are crucial for cytokine receptor signaling in blood formation and immune responses. Mutations and translocations in the JAK genes leading to constitutively active JAK proteins are associated with a variety of hematopoietic malignancies, including the myeloproliferative disorders (JAK2), acute lymphoblastic leukemia (JAK2), acute myeloid leukemia (JAK2, JAK1), acute megakaryoblastic leukemia (JAK2, JAK3) and T-cell precursor acute lymphoblastic leukemia (JAK1). In contrast, loss-of-function mutations of JAK3 and TYK2 lead to immunodeficiency. The role of JAKs as therapeutic targets is starting to expand, as more insights into their structure and activation mechanisms become available.     

PIP kinases and their role in plant tip growing cells

Phosphatidylinositol (4,5) bisphosphate, [PtdIns(4,5)P2], is a signaling lipid involved in many important processes in animal cells such as cytoskeleton organization, intracellular vesicular trafficking, secretion, cell motility, regulation of ion channels, and nuclear signaling pathways. In the last years PtdIns(4,5)P2 and its synthesizing enzyme, phosphatidylinositol phosphate kinase (PIPK), has been intensively studied in plant cells, revealing a key role in the control of polar tip growth. Analysis of the PIPK members from Arabidopsis thaliana, Oryza sativa and Physcomitrella patens showed that they share some regulatory features with animal PIPKs but also exert plant-specific modes of regulation. This review aims at giving an overview on the PIPK family from Arabidopsis thaliana and Physcomitrella patens. Even though their basic structure, modes of activation and physiological role is evolutionary conserved, modules responsible for plasma membrane localization are distinct for different PIPKs, depending on differences in physiological and/or developmental status of cells, such as polarized and non-polarized.     

Mitogen-activated protein kinases and their role in regulation of cellular processes

Mitogen-activated protein kinases (MAPKs) are evolutionary conserved enzymes connecting cell-surface receptors to critical regulatory targets within cells. The three major MAPK cascades are known, the extracellular signal-regulated protein kinase (ERK) cascade, c-Jun amino-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) cascade and p38-MAPK cascade. This paper is focused on characterization of these MAPK cascades in terms of their distribution and biological role in some pathological processes (apoptosis, hypertrophy) with a special orientation on the role of MAPKs in cardiovascular system during ischemia/reperfusion.     

JAK protein tyrosine kinases: their role in cytokine signalling

Protein tyrosine kinases (PTKs) are integral components of the cellular machinery that mediates the transduction and/or processing of many extra- and intracellular signals. Members of the JAK family of intracellular PTKs (JAK1, JAK2 and TYK2) are characterized by the possession of a PTK-related domain and five additional homology domains, in addition to a classical PTK domain. An important breakthrough in the understanding of JAK kinases function(s) has come from the recent observations that many cytokine receptors compensate for their lack of a PTK domain by utilizing members of the JAK family for signal transduction.     

Bioactive molecules in milk and their role in health and disease: the role of transforming growth factor-beta

Human breast milk is rich in nutrients, hormones, growth factors and immunoactive molecules, which influence the growth, development and immune status of the newborn infant. Although several of these factors are also present in bovine milk, the greater susceptibility of the formula-fed infant to infection and disease and the development of allergy is often attributed to the reduced level of protective factors in milk formulas. Nevertheless, modifying manufacturing processes may preserve the biological activity of some bioactive molecules in end products. Transforming growth factor (TGF)-beta is one such molecule. TGF-beta is a polypeptide, which has been described in both human and bovine milk. It is implicated in many processes, including epithelial cell growth and differentiation, development, carcinogenesis and immune regulation. The present article discusses the biological activity of TGF-beta2 that has been preserved and activated in a cow's milk-based product. More specifically, it addresses possible mechanisms of action in the intestinal lumen and speculates on how milk products containing naturally occurring TGF-beta2 could be exploited in functional foods for the infant or as therapies for specific intestinal diseases.     

Janus kinases affect thrombopoietin receptor cell surface localization and stability

The thrombopoietin receptor (TpoR) regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation. TpoR signals by activating Janus kinases JAK2 and Tyk2. Here we show that, in addition to signaling downstream from the activated TpoR, JAK2 and Tyk2 strongly promote cell surface localization and enhance total protein levels of the TpoR. This effect is caused by stabilization of the mature endoglycosidase H-resistant form of the receptor. Confocal microscopy indicates that TpoR colocalizes partially with recycling transferrin in Ba/F3 cells. The interaction with JAK2 or Tyk2 appears to protect the receptor from proteasome degradation. Sequences encompassing Box1 and Box2 regions of the receptor cytosolic domain and an intact JAK2 or Tyk2 FERM domain are required for these effects. We discuss the relevance of our results to the reported defects of TpoR processing in myeloproliferative diseases and to the mechanisms of Tpo signaling and clearance via the TpoR.     

Trypsins and their role in carcinoma growth

There are more than 100 distinct types of cancer, and subtypes can be found within specific organs. Cancer progression is a complex multi-step process. These steps reflect alterations that drive the progressive transformation of normal cells into highly malignant ones. One critical step in tumor growth and invasion is the proteolytic processing of the extracellular matrix environment. The degradation of the extracellular matrix not only enables cell migration, invasion, and metastasis formation, but also affects cell behavior in multiple ways; on one hand by cleaving extracellular matrix bound growth factors and on the other hand by inhibiting angiogenesis into the tumor by liberating cryptic endogenous inhibitors of angiogenesis. Serine proteases and matrix metalloproteases are families of proteolytic enzymes involved in physiological and pathological extracellular matrix and basement membrane processing. In this review, we will focus on the role and activation of trypsinogens, a family of serine proteases, in cancer progression.     

Cyclin dependent kinases and their role in regulation of plant cell cycle

Plants have capability to optimize its architecture by using CDK pathways. It involves diverse types of cyclin dependent kinase enzymes (CDKs). CDKs are classified in to eight classes (CDKA to CDKG and CKL) based on the recognized cyclin-binding domains. These enzymes require specific cyclin proteins to get activated. They form complex with cyclin subunits and phosphorylate key target proteins. Phosphorylation of these target proteins is essential to drive cell cycle further from one phase to another phase. During cell division, the activity of cyclin dependent kinase is controlled by CDK interactor/inhibitor of CDKs (ICK) and Kip-related proteins (KRPs). They bind with specific CDK/cyclin complex and help in controlling CDKs activity. Since cell cycle can be progressed further only by synthesis and destruction of cyclins, they are quickly degraded using ubiquitination-proteasome pathway. Ubiquitylation reaction is followed by DNA duplication and cell division process. These two processes are regulated by two complexes known as Skp1/cullin/F-box (SCF)-related complex and the anaphase-promoting complex/cyclosome (APC/C). SCF allows cell to enter from G1 to S phase and APC/C allows cell to enter from G2 to M phase. When all these above processes of cell division are going on, genes of cyclin dependent kinases gets activated one by one simultaneously and help in regulation of CDK pathways. How cell cycle is regulated by CDKs is discussed.     

Hanging in the balance. KIR and their role in disease

The killer cell immunoglobulin-like receptors (KIR) are a recently discovered family of activating and inhibitory receptors that control natural killer (NK) cell function. KIR exist as a diverse family of receptors that have evolved rapidly by both gene duplication and recombination events. These findings were unexpected for a family of genes involved primarily in the innate immune response. These findings together with the observation that several of these genes have human leukocyte antigen (HLA) class I ligands, have led to a flurry of investigation into how KIR participate in viral infections, autoimmune diseases and malignancies. This review summarizes the major features of these genes and discusses how they may be involved in both disease pathogenesis and its amelioration.     

Phenylaminopyrimidines as inhibitors of Janus kinases (JAKs)

A series of phenylaminopyrimidines has been identified as inhibitors of Janus kinases (JAKs). Development of this initial series led to the potent JAK2/JAK1 inhibitor CYT387 (N-(cyanomethyl)-4-[2-[[4-(4-morpholinyl)phenyl]amino]-4-pyrimidinyl]-benzamide). Details of synthesis and SAR studies of these compounds are reported.     

The role of protein kinases in the regulation of plant growth and development

We review the role of protein kinases in plant hormone-mediatedsignalling, nutrient signalling and cell cycle control and in the crosstalkbetween these different contributors to plant growth regulation. The areas ofhormone-mediated signalling covered include ABA-mediated responses to osmoticstress, wounding and pathogen attack, as well as ethylene and cytokininsignalling pathways. These areas involve members of several major protein kinasefamilies, including the SNFl-related protein kinase-2 (SnRK2) subfamily, thecalcium-dependent protein kinase (CDPK) family, the mitogen activated protein(MAP) kinase family, the glycogen synthase kinase (GSK)- 3/shaggy family and thereceptor-like protein kinase (RPK) family. In the section on nutrient signallingwe review the role of SnRK1 protein kinases in the global regulation of carbonmetabolism, including aspects of sugar sensing and assimilate partitioning, andwhat is known about nitrogen and sulphur nutrient signalling. In the cell cyclesection, we summarise progress in the elucidation of cell cycle control systemsin plants and discuss the interaction between cell cycle control anddevelopment. We expand further on the hypothesis of crosstalk between differentsignalling pathways in a separate section in which we discuss evidence forinteraction between plant growth regulators and the cell cycle, betweendifferent nutrient signalling pathways, between nutrient and cell cyclesignalling and between nutrient and ABA signalling.     

Janus kinase inhibitors role in bone remodeling

Janus kinases (JAKs) play a pleiotropic role in several important physiological processes, such as cell maturation, cell proliferation, and cell death, via providing transmission signals from several molecules, such as cytokines, interferons, hormones, and growth factors, to the nucleus. Bone physiology and remodeling are markedly influenced by proinflammatory cytokines. Among them, interleukin-1 (IL-1) and IL-6 are considered potent stimulator of bone resorption. Several cytokine receptors, such as IL-6 receptors, are characterized by tyrosine kinases of the JAK family associated with their intracellular domains. There is an emerging interest in the effects of JAKs inhibition on the cells involved in bone remodeling. JAK inhibitors represent a new class of molecules involved in the therapy of numerous immune-mediated inflammatory diseases. In this review, we want to focus on the role of JAKs inhibitors on bone remodeling and on RANKL-RANK-OPG signal and inflammatory cytokines which are involved in the regulation of bone cells, such as osteoblasts and osteoclasts.