Two axes in platelet-derived growth factor signaling: tyrosine phosphorylation and reactive oxygen species

The tyrosine phosphorylation cascade is a hallmark of platelet-derived growth factor (PDGF)- induced signal transduction. The amplitude and propagation of the tyrosine phosphorylation signal relies on the balance between tyrosine kinase and tyrosine phosphatase. The tyrosine kinase is latent in the absence of stimulation, whereas the tyrosine phosphatase is highly and constitutively active. Therefore, the kinase activation should be accompanied by temporal and spatial inactivation of tyrosine phosphatase to achieve the robust amplification of tyrosine phosphorylation. For the past decade, reactive oxygen species have been receiving a great deal of attention with regard to their ability to shut down tyrosine phosphatase activities in a reversible manner. In this article, the crosstalk between tyrosine phosphorylation and reactive oxygen species in PDGF signaling is discussed. Received 2 October 2006; received after revision 13 November 2006; accepted 27 November 2006     

Low molecular weight protein tyrosine phosphatases: small,but smart

Low molecular weight protein tyrosine phosphatases (LMW-PTPs) are a family of 18-kDa enzymes involved in cell growth regulation. Despite very limited sequence similarity to the PTP superfamily, they display a conserved signature motif in the catalytic site. LMW-PTP associates and dephosphorylate many growth factor receptors, such as platelet-derived growth factor receptor (PDGF-r), insulin receptor and ephrin receptor, thus downregulating many of the tyrosine kinase receptor functions that lead to cell division. In particular, LMW-PTP acts on both growth-factor-induced mitosis, through dephosphorylation of activated PDGF-r, and on cytoskeleton rearrangement, through dephosphorylation of p190RhoGAP and the consequent regulation of the small GTPase Rho. LMW-PTP activity is modulated by tyrosine phosphorylation on two specific residues, each of them with specific characteristics. LMW-PTP activity on specific substrates depends also on its localization. Moreover, LMW-PTP is reversibly oxidized during growth factor signaling, leading to inhibition of its enzymatic activity. Recovery of phosphatase activity depends on the availability of reduced glutathione and involves the formation of an S–S bridge between the two catalytic site cysteines. Furthermore, studies on the redox state of LMW-PTP in contact-inhibited cells and in mature myoblasts suggest that LMW-PTP is a general and versatile modulator of growth inhibition. Received 17 January 2002; received after revision 22 March 2002; accepted 26 March 2002     

Receptor and nonreceptor protein tyrosine phosphatases in the nervous system

Protein tyrosine phosphatases (PTPs) have emerged as a new class of signaling molecules that play important roles in the development and function of the central nervous system. They include both tyrosine-specific and dual-specific phosphatases. Based on their cellular localization they are also classified as receptor-like or intracellular PTP. However, the intracellular mechanisms by which these PTPs regulate cellular signaling pathways are not well understood. Evidence gathered to date provides some insight into the physiological function of these PTPs in the nervous system. In this review, we outline what is currently known about the functional role of PTPs expressed in the brain.Received 31 March 2003; received after revision 7 May 2003; accepted 22 May 2003     

Histamine deficiency suppresses murine haptoglobin production and modifies hepatic protein tyrosine phosphorylation

Histidine decarboxylase (HDC) synthesizes endogenous histamine from histidine in mammals. HDC- deficient mice (HDC-/-), if kept on a histamine-free diet, have no histamine in their tissues. HDC-/- mice show multiple phenotypes. In this study we show that both the constitutively expressed and turpentine-induced level of an acute-phase protein, haptoglobin, is significantly lower in the serum of HDC-/- mice compared to that of wild-type animals. This effect was abolished if HDC gene-targeted mice received histamine-rich food. No differences were found when lipopolysaccharide (LPS) was used to induce the acute-phase reaction. Using specific antibodies to phosphorylated tyrosine, we showed that protein tyrosine phosphorylation (Y-P) of ~50- and 26- to 27-kDa liver proteins is significantly decreased in HDC-/- mice, but that the difference was largely diminished if the animals were kept on a histamine-rich diet, suggesting that the phenotype with lower haptoglobin production is diet inducible. Upon in vivo treatment with LPS, Y-P band intensity decreased, regardless of the presence or absence of histamine. Identification of elements of the signalling pathway with decreased phosphorylation may elucidate the molecular background of the effect of endogenous histamine in the hepatic acute-phase reaction. Received 14 February 2001; received after revision 28 March 2001; accepted 4 April 2001     

Insulin receptors: Structure and function

Summary and conclusions The recent characterization of the human insulin receptor structure and its intrinsic tyrosine kinase activity represent major advances in our understanding of the mechanism of insulin action. It is reasonable to think that the insulin-induced autophosphorylation and activation of its receptor kinase represent an important event in the action of insulin on cell metabolism and growth. The fundamental research reviewed may be followed by the discovery of molecular receptor defects in clinical syndromes of insulin resistance.     

Regulation of mitochondrial oxidative phosphorylation by second messenger-mediated signal transduction mechanisms

The mitochondrial oxidative phosphorylation system is responsible for providing the bulk of cellular ATP molecules. There is a growing body of information regarding the regulation of this process by a number of second messenger-mediated signal transduction mechanisms, although direct studies aimed at elucidating this regulation are limited. The main second messengers affecting mitochondrial signal transduction are cAMP and calcium. Other second messengers include ceramide and reactive oxygen species as well as nitric oxide and reactive nitrogen species. This review focuses on available data on the regulation of the mitochondrial oxidative phosphorylation system by signal transduction mechanisms and is organised according to the second messengers involved, because of their pivotal role in mitochondrial function. Future perspectives for further investigations regarding these mechanisms in the regulation of the oxidative phosphorylation system are formulated. Received 11 December 2005; received after revision 14 January 2006; accepted 6 February 2006     

The Janus kinase family of protein tyrosine kinases and their role in signaling

In the early 1990s, the search for protein kinases led to the discovery of a novel family of non-receptor tyrosine kinases, the Janus kinases or JAKs. These proteins were unusual because they contained two kinase homology domains and no other known signaling modules. It soon became clear that these were not ‘just another’ type of kinase. Their ability to complement mutant cells insensitive to interferons and to be activated by a variety of cytokines demonstrated their central signaling function. Now, as we approach the end of the decade, it is evident from biochemical studies to knockout mice that JAKs play non-redundant functions in development, differentiation, and host defense mechanisms. Here, recent progress is reviewed, with particular emphasis on structure-function studies aimed at revealing how this family of tyrosine kinases is regulated.     

Expression of the Stp1 LMW-PTP and inhibition of protein CK2 display a cooperative effect on immunophilin Fpr3 tyrosine phosphorylation and <Emphasis Type="Italic">Saccharomyces cerevisiae</Emphasis> growth

Although the yeast genome does not encode bona fide protein tyrosine kinases, tyrosine-phosphorylated proteins are numerous, suggesting that besides dual-specificity kinases, some Ser/Thr kinases are also committed to tyrosine phosphorylation in Saccharomyces cerevisiae. Here we show that blockage of the highly pleiotropic Ser/Thr kinase CK2 with a specific inhibitor synergizes with the overexpression of Stp1 low-molecular-weight protein tyrosine phosphatase (PTP) in inducing a severe growth-defective phenotype, consistent with a prominent role for CK2 in tyrosine phosphorylation in yeast. We also present in vivo evidence that immunophilin Fpr3, the only tyrosine-phosphorylated CK2 substrate recognized so far, interacts with and is dephosphorylated by Spt1. These data disclose a functional correlation between CK2 and LMW-PTPs, and suggest that reversible phosphorylation of Fpr3 plays a role in the regulation of growth rate and budding in S. cerevisiae.Received 15 January 2004; received after revision 20 February 2004; accepted 4 March 2004     

Conservation,evolution, and specificity in cellular control by protein phosphorylation

The glycolytic control enzyme phosphofructokinase from the parasitic nematodeAscaris lumbricodies is regulated by reversible phosphorylation. The enzyme is phosphorylated by an atypical cyclic adenosine monophosphate (cAMP)-dependent protein kinase whose substrate specificity deviates from that of the mammalian protein kinase. This variation is explained by structural peculiarities on the surface part of the catalytic groove of the protein kinase. Also, the protein phosphatases responsible for the reversal of phosphorylation appear to act specifically in glycolysis and are different from those participating in regulation of glycogenolysis.     

Regulation of nicotinic acetylcholine receptors by tyrosine kinases in the peripheral and central nervous system: same players, different roles

Nicotinic acetylcholine receptors (nAChRs) exist in many subtypes and are found in the peripheral and central nervous system where they mediate or modulate synaptic transmission. We review how tyrosine phosphorylation and kinases regulate muscle and neuronal nAChRs. Interestingly, although some of the same kinase players interact with the various receptor subtypes, the functional consequences are different. While concerted action of MuSK, Abl- and Src-family kinases (SFKs) regulates the synaptic distribution of nAChRs at the neuromuscular junction, SFKs activate heteromeric neuronal nAChRs in adrenal chromaffin cells, thereby enhancing catecholamine secretion. In contrast, the activity of homomeric neuronal nAChRs, as found in the hippocampus, is negatively regulated by tyrosine phosphorylation and SFKs. It appears that tyrosine kinases provide the means to regulate all nAChRs; but the functional consequences, even those caused by the same kinase family, are specific for each receptor subtype and location. Received 21 February 2006; received after revision 24 July 2006; accepted 30 August 2006     

AMP-activated protein kinase in skeletal muscle: From structure and localization to its role as a master regulator of cellular metabolism

The AMP-activated protein kinase (AMPK) is a metabolite sensing serine/threonine kinase that has been termed the master regulator of cellular energy metabolism due to its numerous roles in the regulation of glucose, lipid, and protein metabolism. In this review, we first summarize the current literature on a number of important aspects of AMPK in skeletal muscle. These include the following: (1) the structural components of the three AMPK subunits (i.e. AMPKα, β, and γ), and their differential localization in response to stimulation in muscle; (2) the biochemical regulation of AMPK by AMP, protein phosphatases, and its three known upstream kinases, LKB1, Ca²⁺/calmodulin-dependent protein kinase kinase (CaMKK), and transforming growth factor-β-activated kinase 1 (TAK1); (3) the pharmacological agents that are currently available for the activation and inhibition of AMPK; (4) the physiological stimuli that activate AMPK in muscle; and (5) the metabolic processes that AMPK regulates in skeletal muscle. Received 04 May 2008; received after revision 14 June 2008; accepted 14 July 2008