Signal transduction: Gyrating protein kinases.

Recently determined structures have linked histidine kinases with class II topoisomerases, the DNA repair enzyme MutL and the molecular chaperone Hsp90. This surprising finding may foreshadow a shift in our understanding of energy coupling mechanisms in signal transduction networks.     

Signal transduction in photoreceptor histidine kinases

Two‐component systems (TCS) constitute the predominant means by which prokaryotes read out and adapt to their environment. Canonical TCSs comprise a sensor histidine kinase (SHK), usually a transmembrane receptor, and a response regulator (RR). In signal‐dependent manner, the SHK autophosphorylates and in turn transfers the phosphoryl group to the RR which then elicits downstream responses, often in form of altered gene expression. SHKs also catalyze the hydrolysis of the phospho‐RR, hence, tightly adjusting the overall degree of RR phosphorylation. Photoreceptor histidine kinases are a subset of mostly soluble, cytosolic SHKs that sense light in the near‐ultraviolet to near‐infrared spectral range. Owing to their experimental tractability, photoreceptor histidine kinases serve as paradigms and provide unusually detailed molecular insight into signal detection, decoding, and regulation of SHK activity. The synthesis of recent results on receptors with light‐oxygen‐voltage, bacteriophytochrome and microbial rhodopsin sensor units identifies recurring, joint signaling strategies. Light signals are initially absorbed by the sensor module and converted into subtle rearrangements of α helices, mostly through pivoting and rotation. These conformational transitions propagate through parallel coiled‐coil linkers to the effector unit as changes in left‐handed superhelical winding. Within the effector, subtle conformations are triggered that modulate the solvent accessibility of residues engaged in the kinase and phosphatase activities. Taken together, a consistent view of the entire trajectory from signal detection to regulation of output emerges. The underlying allosteric mechanisms could widely apply to TCS signaling in general.     

Signal transduction in monocytes: the role of zinc ions

The availability of zinc has a regulatory role in the immune system. It can have either pro- or anti-inflammatory effects, which both seem to be a consequence of a direct interaction of zinc with the cytokine secretion by monocytes. In this review, the molecular basis for this effect, the interaction of zinc with the signal transduction of monocytes, is discussed. In particular, zinc seems to activate or inhibit several signaling pathways that interact with the signal transduction of pathogen sensing receptors, the so-called Toll-like receptors (TLR), which sense pathogen-derived molecular structures and, upon activation, lead to secretion of pro-inflammatory cytokines. The interaction of zinc with protein tyrosine phosphatases and protein kinase C, and a direct modulation of lipopolysaccharide binding to its receptor (TLR-4) all result in enhanced cytokine production. On the other hand, a complex interaction between zinc, NO and cyclic nucleotide signaling, and inhibition of interleukin-1 receptor associated kinase-1, and inhibitor of kappa B kinase all counteract the production of pro-inflammatory cytokines. A role for the zinc binding protein metallothionein as a regulator for intracellular zinc signaling is discussed. By acting on all these signaling molecules, the zinc status of monocytes can have a direct effect on inflammation.     

Signal transduction in lemon seedlings in the hypersensitive response against Alternaria alternata: participation of calmodulin,G-protein and protein kinases

The development of an effective hypersensitive response (HR) in any plant system relies, not only in their gene composition and expression, but also on an effective and rapid signal transduction system. Lemon seedlings induce the phenylpropanoid pathway, which results in the de novo biosynthesis of the phytoalexin scoparone, as part of the hypersensitive response against Alternaria alternata. In order to elucidate some of the signaling elements that participate in the development of HR in lemon seedlings, we used several compounds that are known as activators or inhibitors of signal transduction elements in plants or in animal cells. Lemon seedlings treated either with cholera toxin or with phorbol 12-myristate 13-acetate (PMA), in the absence of A. alternata induced phenylalanine ammonia-lyase (PAL, E. C. 4.3.1.5) and the synthesis of scoparone, suggesting the participation of a G-protein and of a serine/threonine kinase, respectively, in signal transduction. The use of trifluoperazine (TFP), W-7, staurosporine, lavendustin A or 2,5-dihydroximethyl cinnamate (DHMC) prevented PAL induction as well as scoparone biosynthesis in response to the fungal inoculation, thus allowing us to infer the participation of Calmodulin (CaM), of serine/threonine and of tyrosine protein kinases (TPK) for signal transduction in Citrus limon in response to A. alternata.     

Signal transduction through the cAMP-dependent protein kinase

Molecular and Cellular Biochemistry - Temporal cellular events responsible for hormonal activation of responses mediated by the cAMP-dependent protein kinase (PKA) have been studied in living...     

Oncogenes,protein tyrosine kinases,and signal transduction

Many oncogenes encode protein tyrosine kinases (PTKs). Oncogenic mutations of these genes invariably result in constitutive activation of these PTKs. Autophosphorylation of the PTKs and tyrosine phosphorylation of their cellular substrates are essential events for transmission of the mitogenic signal into cells. The recent discovery of the characteristic amino acid sequences, of thesrc homology domains 2 and 3 (SH2 and SH3), and extensive studies on proteins containing the SH2 and SH3 domains have revealed that protein tyrosine-phosphorylation of PTKs provides phosphotyrosine sites for SH2 binding and allows extracellular signals to be relayed into the nucleus through a chain of protein-protein interactions mediated by the SH2 and SH3 domains. Studies on oncogenes, PTKs and SH2/SH3-containing proteins have made a tremendous contribution to our understanding of the mechanisms for the control of cell growth, oncogenesis, and signal transduction. This review is intended to provide an outline of the most recent progress in the study of signal transduction by PTKs.     

Signal transduction at a protein synapse

Contraction of the bacteriophage T4 tail in the act of host cell penetration represents a massive structural change powered by conformational free energy. A paper in this issue of Cell by compares cryo-electron microscopic reconstructions of the initial and final states and reveals that the basic underlying mechanism is concerted rigid-body movements of the constituent protein subunits, akin to the tumbling of gears in a lock.     

Signal transduction of bone morphogenetic protein receptors

Bone morphogenetic proteins (BMPs) play a crucial role during all stages of embryonic development. Although only two major signaling pathways have been characterized (the p38 and Smad pathways), the BMP signaling is complex and includes several negative feedback mechanisms. This article reviews the current state of BMP receptor signaling and provides a summary of the crosstalk of the BMP receptor pathway with other major signaling pathways.     

Signal transduction mechanisms in the regulation of protein synthesis

Control of polypeptide synthesis plays an important role in cell proliferation and translation rates generally reflect the growth state of the cultured eukaryotic cell. Physiological regulation of protein synthesis is almost always exerted at the level of polypeptide chain initiation, with the binding of mRNA to the small ribosomal subunit a rate-limiting step in many cell systems. Studies have indicated key roles in the regulation of protein synthesis for the structural features of mRNA molecules and phosphorylation of initiation factors which catalyse this process. This review focusses on translational regulation at the level of mRNA binding to the ribosome and the role of phosphorylation of initiation factors in mediating both quantitative and qualitative control. The identity of putative kinases which may mediate these processes is addressed and a possible model for the role of a transient activation of initiation factors in cell growth or differentiation is presented.     

Signal transduction during liver regeneration: role of insulin and vasopressin.

The relationship between cell proliferation and inositol lipid turnover has been studied by comparing the steady state of inositol derivative metabolism in quiescent and regenerating rat hepatocytes isolated at 4 h (G1 phase of first cell cycle) and 24 h (onset of M phase) after partial hepatectomy. The effect of two hormones able to regulate hepatic regeneration, insulin and vasopressin, has been considered, and the results can be summarized as follows: (i) at 4 h after partial hepatectomy, the precursor incorporation into inositol polyphosphates and the particulate phospholipase C activity increase with respect to quiescent hepatocytes, whereas the content of 11, 4, 5P3 does not change, suggesting an increased turnover of this molecule in this step of cell cycle priming; (ii) 24 h after partial hepatectomy, the radioactivity linked to IP3 and IP4, as well as soluble and particulate phospholipase C activity, and IP3 content increase, suggesting the presence, at the onset of M phase, of second messenger accumulation; (iii) only 24 h after partial hepatectomy, the inositol derivative metabolism is affected by vasopressin; and (iv) insulin exerts a modulatory role on inositol polyphosphate production without involving membrane-bound PLC activity or phosphoinositide hydrolysis. These data suggest that inositol-derived signal molecules are associated with hepatic regeneration; moreover, the metabolic pathway of such compounds seems to be regulated so that only specific inositol phosphates are present in each step of the cell cycle.     

Signal transduction protein array analysis links LRRK2 to Ste20 kinases and PKC zeta that modulate neuronal plasticity

Background

Dominant mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson''s disease, however, the underlying pathogenic mechanisms are poorly understood. Several in vitro studies have shown that the most frequent mutation, LRRK2(G2019S), increases kinase activity and impairs neuronal survival. LRRK2 has been linked to the mitogen-activated protein kinase kinase kinase family and the receptor-interacting protein kinases based on sequence similarity within the kinase domain and in vitro substrate phosphorylation.

Methodology/Principal Findings

We used an unbiased proteomic approach to identify the kinase signaling pathways wherein LRRK2 may be active. By incubation of protein microarrays containing 260 signal transduction proteins we detected four arrayed Ste20 serine/threonine kinase family members (TAOK3, STK3, STK24, STK25) as novel LRRK2 substrates and LRRK2 interacting proteins, respectively. Moreover, we found that protein kinase C (PKC) zeta binds and phosphorylates LRRK2 both in vitro and in vivo.

Conclusions/Significance

Ste20 kinases and PKC zeta contribute to neuronal Tau phosphorylation, neurite outgrowth and synaptic plasticity under physiological conditions. Our data suggest that these kinases may also be involved in synaptic dysfunction and neurite fragmentation in transgenic mice and in human PD patients carrying toxic gain-of-function LRRK2 mutations.