Identification of Drosophila Genes Modulating Janus Kinase/Signal Transducer and Activator of Transcription Signal Transduction

By Mukherjee, Tina; Schäfer, Ulrich et al. | Genetics, March 2006 | Go to article overview

Identification of Drosophila Genes Modulating Janus Kinase/Signal Transducer and Activator of Transcription Signal Transduction


Mukherjee, Tina, Schäfer, Ulrich, Zeidler, Martin P., Genetics


ABSTRACT

The JAK/STAT pathway was first identified in mammals as a signaling mechanism central to hematopoiesis and has since been shown to exert a wide range of pleiotropic effects on multiple developmental processes. Its inappropriate activation is also implicated in the development of numerous human malignancies, especially those derived from hematopoietic lineages. The JAK/STAT signaling cascade has been conserved through evolution and although the pathway identified in Drosophila has been closely examined, the full complement of genes required to correctly transduce signaling in vivo remains to be identified. We have used a dosage-sensitive dominant eye overgrowth phenotype caused by ectopic activation of the JAK/STAT pathway to screen 2267 independent, newly generated mutagenic P-element insertions. After multiple rounds of retesting, 23 interacting loci that represent genes not previously known to interact with JAK/STAT signaling have been identified. Analysis of these genes has identified three signal transduction pathways, seven potential components of the pathway itself, and six putative downstream pathway target genes. The use of forward genetics to identify loci and reverse genetic approaches to characterize them has allowed us to assemble a collection of genes whose products represent novel components and regulators of this important signal transduction cascade.

DEVELOPING cells in vivo are influenced by, and interact with, their surroundings via multiple mechanisms central to which are the signal transduction cascades. Activation of such cascades by extracellular ligands generally converts signals into changes in the gene expression profile of a responding cell. Although only a relatively limited number of such pathways have been identified, these signaling cascades have generally been conserved throughout evolution and are often active at multiple stages of development where they exert a wide range of pleiotropic effects, including cellular growth, proliferation, and differentiation.

The Janus tonase (JAK) /signal transducer and activator of transcription (STAT) pathway is one such signaling cascade. The pathway was first identified in mammals where extensive analysis has led to the development of a canonical model for JAK/STAT signaling in which nonreceptor JAK tyrosine kinases are associated with the intracellular portion of trans-membrane receptors. Following ligand binding to dimerized cytokine receptors the associated JAK molecules become active and auto- and iraws-phosphorylate one another and their receptors. The resulting phospho-tyrosine residues are recognized by the SH2 domain of normally cytosolic STAT proteins, which are recruited to these docking sites before being themselves phosphorylated on a C-terminal tyrosine residue by the JAKs. The activated STATs form homo- and hetero-dimers and translocate to the nucleus, bind to a palindromic DNA recognition sequence, and activate the transcription of pathway target genes (ZEIDLER et al. 200Oa; BROMBERG 2002; KISSELEVA et al. 2002).

In mammals, fourJak molecules have been identified: Jakl, Jak2,Jak3, and tyrosine kinase 2(tyk2). STATs compose a family of seven structurally and functionally related proteins: Statl-4, StatSa, StatSb, and StatG. Stat proteins play a central role in transmitting cell surface cytokine signals into the nucleus and in induceing cellular proliferation, differentiation, and survival signals in multiple hematopoetic cell types. Under normal circumstances, ligand availability and negative feedback mechanisms tightly regulate the cytokine-mediated activation of Stats (BOWMAN et al 2000). However, constitutive activation of multiple Jaks and Stats is associated with diverse leukemias and lymphomas (FRIEDMANN et al 1996; LACRONIQUE et al. 1997; JAMES et al. 2005), resulting in a radical alteration of the gene expression and ligand-independent survival/proliferation of these transformed cells (STERNBERG and GILLILAND 2004). …

The rest of this article is only available to active members of Questia

Already a member? Log in now.

Notes for this article

Add a new note
If you are trying to select text to create highlights or citations, remember that you must now click or tap on the first word, and then click or tap on the last word.
One moment ...
Default project is now your active project.
Project items
Notes
Cite this article

Cited article

Style
Citations are available only to our active members.
Buy instant access to cite pages or passages in MLA 8, MLA 7, APA and Chicago citation styles.

(Einhorn, 1992, p. 25)

(Einhorn 25)

(Einhorn 25)

1. Lois J. Einhorn, Abraham Lincoln, the Orator: Penetrating the Lincoln Legend (Westport, CT: Greenwood Press, 1992), 25, http://www.questia.com/read/27419298.

Note: primary sources have slightly different requirements for citation. Please see these guidelines for more information.

Cited article

Identification of Drosophila Genes Modulating Janus Kinase/Signal Transducer and Activator of Transcription Signal Transduction
Settings

Settings

Typeface
Text size Smaller Larger Reset View mode
Search within

Search within this article

Look up

Look up a word

  • Dictionary
  • Thesaurus
Please submit a word or phrase above.
Print this page

Print this page

Why can't I print more than one page at a time?

Help
Full screen
Items saved from this article
  • Highlights & Notes
  • Citations
Some of your highlights are legacy items.

Highlights saved before July 30, 2012 will not be displayed on their respective source pages.

You can easily re-create the highlights by opening the book page or article, selecting the text, and clicking “Highlight.”

matching results for page

    Questia reader help

    How to highlight and cite specific passages

    1. Click or tap the first word you want to select.
    2. Click or tap the last word you want to select, and you’ll see everything in between get selected.
    3. You’ll then get a menu of options like creating a highlight or a citation from that passage of text.

    OK, got it!

    Cited passage

    Style
    Citations are available only to our active members.
    Buy instant access to cite pages or passages in MLA 8, MLA 7, APA and Chicago citation styles.

    "Portraying himself as an honest, ordinary person helped Lincoln identify with his audiences." (Einhorn, 1992, p. 25).

    "Portraying himself as an honest, ordinary person helped Lincoln identify with his audiences." (Einhorn 25)

    "Portraying himself as an honest, ordinary person helped Lincoln identify with his audiences." (Einhorn 25)

    "Portraying himself as an honest, ordinary person helped Lincoln identify with his audiences."1

    1. Lois J. Einhorn, Abraham Lincoln, the Orator: Penetrating the Lincoln Legend (Westport, CT: Greenwood Press, 1992), 25, http://www.questia.com/read/27419298.

    Cited passage

    Thanks for trying Questia!

    Please continue trying out our research tools, but please note, full functionality is available only to our active members.

    Your work will be lost once you leave this Web page.

    Buy instant access to save your work.

    Already a member? Log in now.

    Search by... Author
    Show... All Results Primary Sources Peer-reviewed

    Oops!

    An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.