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    a certain effector protein can be activated by phosphorylation at a key tyrosine residue. an upstream kinase rapidly phosphorylates this tyrosine in the presence of a signal. however, the kinase also phosphorylates and activates a slow-acting phosphatase that can dephosphorylate the phosphotyrosine. which curve in the following graph would you expect to represent the activity of the effector molecule over time? the input signal is present during the period indicated in gray. the dashed line represents the response in the absence of the phosphatase.

    James

    Guys, does anyone know the answer?

    get a certain effector protein can be activated by phosphorylation at a key tyrosine residue. an upstream kinase rapidly phosphorylates this tyrosine in the presence of a signal. however, the kinase also phosphorylates and activates a slow-acting phosphatase that can dephosphorylate the phosphotyrosine. which curve in the following graph would you expect to represent the activity of the effector molecule over time? the input signal is present during the period indicated in gray. the dashed line represents the response in the absence of the phosphatase. from EN Bilgi.

    Protein tyrosine phosphatases as wardens of STAT signaling

    Signaling by signal transducers and activators of transcription (STATs) is controlled at many levels of the signaling cascade. Protein tyrosine phosphatases (PTPs) regulate STAT activation at several layers, including direct pSTAT dephosphorylation in ...

    JAKSTAT. 2014; 3(1): e28087.

    Published online 2014 Feb 20. doi: 10.4161/jkst.28087

    PMCID: PMC3995736 PMID: 24778927

    Protein tyrosine phosphatases as wardens of STAT signaling

    Frank-D Böhmer 1 ,* and Karlheinz Friedrich 2

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    This article has been cited by other articles in PMC.

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    Abstract

    Signaling by signal transducers and activators of transcription (STATs) is controlled at many levels of the signaling cascade. Protein tyrosine phosphatases (PTPs) regulate STAT activation at several layers, including direct pSTAT dephosphorylation in both cytoplasm and nucleus. Despite the importance of this regulation mode, many aspects are still incompletely understood, e.g., the identity of PTPs acting on certain members of the STAT family. After a brief introduction into the STAT and PTP families, we discuss here the current knowledge on PTP mediated regulation of STAT activity, focusing on the interaction of individual STATs with specific PTPs. Finally, we highlight open questions and propose important tasks of future research.

    Keywords: signal transducer and activator of transcription, STAT, dephosphorylation, protein tyrosine phosphatase, PTP

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    General Introduction

    The JAK-STAT pathway is a fundamental intracellular signaling cascade that transduces multiple signals of crucial importance for development and homeostasis in animals. While its most elaborate versions are operative in mammals, elementary JAK-STAT systems also exist in Drosophila melanogaster and even in the slime mold Dictyostelium discoideum,1 pointing to an early origin in evolutionary terms.

    In higher animals, the JAK-STAT pathway is central for the transmission of signals from numerous cytokine and growth factor receptors to the cell nucleus. STAT activation by phosphorylation through Janus kinases and other cytoplasmic tyrosine kinases mediates cell proliferation, differentiation, cell migration and apoptosis. These processes are essential determinants for the development of blood and immune cells as well as of many other tissues throughout the organism (reviewed in refs. 2 and 3). Not surprisingly, aberrant STAT signaling is associated with immune disorders and neoplasias of both hematopoietic and solid tissues.

    The canonical JAK-STAT signaling pathway employs only few components and relies on relatively simple mechanisms. Basically, STAT proteins are first recruited to activated receptors via interaction between the STATs’ SH2 domains and tyrosine phophorylated docking sites. Next, STATs become phosphorylated themselves at a critical, conserved tyrosine residue, leading to their release from the receptor complex and dimerization of STATs through reciprocal contact between SH2 domains and phosphotyrosine moieties and their local environment. As a consequence, these so-called “parallel” STAT dimers become capable of crossing the nuclear membrane and reach chromatin, where they bind specific cognate DNA elements and participate in complex gene regulation processes (for a recent review see ref. 4). Obviously, the JAK-STAT pathway represents an immediate means of linking extracellular signals to a transcriptional response and, hence, requires tight control. While mechanisms underlying STAT tyrosine phosphorylation have been extensively characterized, less work has been devoted to the control of STAT-mediated signaling by dephosphorylation. These reactions, however, are essential to ensure proper amplitudes and kinetics of STAT activation.5 Dephosphorylation adds a layer of complexity to the control of JAK-STAT pathways in that it can specifically direct physiological signals by addressing different phosphotyrosine bearing motifs of STATs or the activating receptors and kinases. Moreover, it involves different protein tyrosine phosphatases (PTPs) in different contexts. In line with the importance of PTP-mediated regulation, failure of correct PTP function is associated with characteristic states of disease.6

    In this review, we will give an overview of dephosphorylation-based mechanisms regulating JAK-STAT signaling. After a brief discussion of upstream events such as the control of receptor and JAK phosphorylation, we focus on reactions which directly affect the STAT proteins, limiting the discussion to phosphotyrosine dephosphorylation. Reversible serine phosphorylation of STATs also contributes to gene regulation,7 but there is as yet only little information about underlying mechanisms.

    We will first provide a brief introduction to STAT and PTP families. We will then discuss PTP-mediated regulation at different levels, with main emphasis on regulation of the individual STAT family members and, in the concluding section, highlight open questions and important areas of future research.

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    The STATs and Their Activation–Inactivation Cycle

    The mammalian family of STAT factors consists of seven members (STAT1, STAT2, STAT3, STAT4, STAT5A and B, and STAT6). Activation of STATs (Fig. 1) is primarily driven by ligand-stimulated cytokine receptors, and, though described for fewer examples, by receptor tyrosine kinases (RTKs). The intracellular domains of cytokine receptors, which can come as homo- or heterodimers in their activated state, are associated with Janus kinases (JAKs). JAKs represent a family of cytoplasmic tyrosine kinases which comprises four mammalian members (JAK1, JAK2, JAK3, and TYK2), and each cytokine receptor subunit recruits with preference one of the JAKs. Upon ligand-induced receptor crosslinking, JAKs become activated by juxtaposition and mutual tyrosine phosphorylation, which leads to JAK-mediated phosphorylation of receptor-borne tyrosine residues. As a result, phosphotyrosine (pTyr)-based docking sites for SH2 domains are formed, a prerequisite for the recruitment of specific STAT proteins. STATs subsequently become tyrosine phosphorylated by the persistent JAK activity within the signaling complex. Via pTyr–SH2 domain interaction, STATs are engaged in homo- or heterodimerization and consequently become released from the receptor and undergo conformational changes. As a consequence, nuclear localization signals become accessible, enabling STAT dimers to translocate into the nucleus via the Ran nuclear import pathway, to bind to palindromic cognate sequence elements in the DNA and to participate in transcriptional regulation (for a recent review see ref. 4).

    Source : www.ncbi.nlm.nih.gov

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    TEST THREE CELL BIOLOGY Flashcards

    Start studying TEST THREE CELL BIOLOGY. Learn vocabulary, terms, and more with flashcards, games, and other study tools.

    TEST THREE CELL BIOLOGY

    Organelles through the secretory pathway exhibit differential pH. What would NOT be the reason for this differential pH?

    (A) The differential pH in Golgi pulls it towards the nucleus so that Golgi location is always next to the nucleus

    (B) Lysosome keeps lower pH to facilitate the hydrolysis of macromolecules

    (C) pH in Golgi is lower than that of ER, which helps retrieving ER resident proteins

    (D) Acidic lysosome lumen triggers the activation of various hydrolases

    (E) All of the above are correct

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    (A) The differential pH in Golgi pulls it towards the nucleus so that Golgi location is always next to the next to the nucleus

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    Which of the following is TRUE about ER Golgi traffic?

    (A) ER resident proteins always stay in ER lumen

    (B) ER-derived vesicles are targeted to cis-Golgi

    (C) Properly processed membrane proteins in trans-Golgi is bound for ER

    (D) Lumen of cis-, medial-, trans-Golgi is continuous

    (E) All of the above are correct

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    (B) ER-derived vesicles are targeted to cis-Golgi

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    Terms in this set (22)

    Organelles through the secretory pathway exhibit differential pH. What would NOT be the reason for this differential pH?

    (A) The differential pH in Golgi pulls it towards the nucleus so that Golgi location is always next to the nucleus

    (B) Lysosome keeps lower pH to facilitate the hydrolysis of macromolecules

    (C) pH in Golgi is lower than that of ER, which helps retrieving ER resident proteins

    (D) Acidic lysosome lumen triggers the activation of various hydrolases

    (E) All of the above are correct

    (A) The differential pH in Golgi pulls it towards the nucleus so that Golgi location is always next to the next to the nucleus

    Which of the following is TRUE about ER Golgi traffic?

    (A) ER resident proteins always stay in ER lumen

    (B) ER-derived vesicles are targeted to cis-Golgi

    (C) Properly processed membrane proteins in trans-Golgi is bound for ER

    (D) Lumen of cis-, medial-, trans-Golgi is continuous

    (E) All of the above are correct

    (B) ER-derived vesicles are targeted to cis-Golgi

    Which type of signaling is a type of signaling over long distance by use of hormones are signaling molecules that are released into the bloodstream so that they can travel all throughout the body?

    (A) Endocrine signaling

    (B) Paracrine signaling

    (C) Contact-dependent signaling

    (D) Synaptic signaling

    (E) None of the above

    (A) Endocrine signaling

    Which of the following is NOT true in regard to Ca2+ in the cell?

    (A) A frequency of Ca2+ oscillation can code a specific cellular response

    (B) Increased local Ca2+ opens nearby IP3 and Ryanodine receptors by calcium-induced calcium release

    (C) Ca2+ influx upon membrane depolarization triggers synaptic vesicle fusion by releasing inhibitors from SNARE complex

    (D) Increased intracellular Ca2+ triggers skeletal muscle contraction by exposing myosin binding sites on microfilament

    (E) Ca2+ directly activates PKA by releasing it from inhibitory subunits

    (E) Ca2+ directly activates PKA by releasing it from inhibitory subunits

    The critical concentration (Cc) for microfilament in test tube is around 0.2 uM. The cellular concentration of actin is above 20 uM, far greater than Cc of microfilament. F-actin elongation is not prevalent inside of living cells. Which of the following can explain this discrepancy?

    (A) Most of Actin monomers are not available for polymerization in living cells.

    (B) In living cells, most of Actin is loaded with ADP

    (C) At a concentration above Cc, elongation reaction is not favorable

    (D) In living cells, treadmilling effect largely limits microfilament growth

    (A) Most of Actin monomers are not available for polymerization in living cells.

    The increased Ca2+ spike frequency is translated into a gradual increase in the activation of CaM-kinases. Which of the following is TRUE about this decoding process?

    (A) Calmodulin contains multiple Ca2+ binding sites that displays frequency-dependent binding properties

    (B) CaM-kinase undergoes autophosphorylation that acts as a molecular memory

    (C) At lower Ca2+ frequency, CaM-Kinase cannot be activated

    (D) The oscillation of intracellular Ca2+ concentration deactivates CaM-kinase

    (E) Higher Ca2+ frequency induces the accumulation of activated PKC that in turn activate CaM-kinase

    (B) CaM-kinase undergoes autophosphorylation that acts as a molecular memory

    Progesterone is a relatively large uncharged steroid hormone. Therefore, it will not be able to pass easily through the plasma membrane

    (A) True (B) False (B) False

    Lysosomes are the principal site of cellular digestion. They...

    (A) Are formed from endocytosis

    (B) Contain independent genome like mitochondria

    (C) Require maturation process starting from early endosome

    (D) A and B (E) A and C

    (C) Require maturation process starting from early endosome

    Which endocytic process is best depicted in the following schematic diagram?

    (A) Receptor-mediated endocytosis

    (B) Pinocytosis

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