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SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION (STATs)
Signal Transducers and Activators of Transcription (STATs) Activation and Biology
Edited by
Pravin B. Sehgal New York University School of Medicine, U.S.A .
David E. Levy New York University School of Medicine, U.S.A .
and
Toshio Hirano Osaka U niversity, Japan
SPRINGER-SCIENCE+BUSINESS MEDIA, B.V.
A C.I.P. Catalogue record for this book is available from the Library of Congress.
ISBN 978-90-481-6421-9 ISBN 978-94-017-3000-6 (eBook)
DOI 10.1007/978-94-017-3000-6
Printed an acid-Iree paper
All Rights Reserved © 2003 Springer Science+Business Media Dordrecht Originally published by Kluwer Academic Publishers in 2003 Softcover reprint of the hardcover 1 st edition 2003
No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permis sion from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work.
FOREWORD
The year 2003 marks the tenth anniversary of the first use of the acronym "Stat" (also written "STAT") in the scientific literature for a family of transcription factors which rapidly transduce cytokine- and growth factorelicited signals from the plasma membrane to the cell nucleus thereby activating gene transcription (thus, .s.ignal Transducers and Activators of Transcription). From those beginnings, the field of STAT transcription factors, their related regulatory molecules and their biology has grown exponentially in many different directions.
In recognition of the rapid growth and broad scope of the STAT transcription factor field today, and to celebrate the tenth anniversary of the use of this term in the scientific literature, Kluwer Academic Publishers B.V. requested us to compile a volume on STAT transcription factors that could serve as an overview of this burgeoning area. Thus, we wanted a volume that would serve as a reference for what is known about STAT proteins and their biology, would describe the current state of ongoing research in this broad area, and would look toward the future to try to predict the discoveries that lie ahead. Our charge was to seek out the very best experts in the field and to coax them to briefly summarize their areas of expertise. We hope the end result of this endeavor will prove useful to both the novice and the expert in that it will provide within the covers of one book not only a didactic overview of the STAT transcription factor field, but also a summary of past literature, current developments, and new uncharted, perhaps controversial, ideas and questions about STAT activation and biology. In order to preserve the particular style of each contributor and to give the book a unique flavor, we agreed that each chapter could be somewhat slanted in the form of a personal essay and in some cases requested even overlapping contributions from experts with different points of view.
We were pleasantly surprised by the enthusiasm with which this project was received by our colleagues. We are grateful to all of the contributors who have collectively put their best foot forward and helped produce a memorable book. We thank them all. Weare sure that your readers will appreciate each and every contribution in this volume.
We dedicate this book to Jim Darnell. Jim has not only contributed enormously to this entire field from its inception through to the present (and we assume will into the future), coined the term STAT along with his wife
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Jane, but has also been a mentor, a colleague and a friend to many of the contributors to this volume. PBS and DEL, as Jim's former predoctoral and postdoctoral trainees respectively, owe a particular debt of gratitude for the way that the "Darnell Lab" touched our lives.
We thank Clare Nehammer, our Publishing Editor at Kluwer, who has been instrumental in moving this project forward with efficiency and great speed. We also appreciate the assistance of Esther Verdries at Kluwer who has answered many manuscript handling and style-related questions sent her way by all of us with dispatch and clarity. Moreover, we are grateful for the invaluable assistance of Mehul Shah in collating and compiling this book.
PBS would like to pay special tribute to his friends Elyse S. Goldweber, Josephine Lauriello, Michele Tortorelli and Sansar C. Sharma without whose collective help during critical moments during the last year this project would not have materialized.
We consider it a personal honor to have had the opportunity to compile "The STAT book." We thank our colleagues for their magnificent contributions.
June 12, 2003 Pravin B. Sehgal
David E. Levy Toshio Hirano
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TABLE OF CONTENTS
Foreword
Color Plates
Introduction: a brief history ofthe STATs and a glance at the future
James E. Darnell, Jr.
SECTION I STAT PROTEINS AND THEIR REGULATORS
The STAT protein family Markus H. Heim
The Janus kinase protein family Pipsa Saharinen and Olli Silvennoinen
Structural bases ofreceptor-JAK-STAT interactions
Peter C. Heinrich, Iris Behrmann, Serge Haan, Heike M. Hermanns, Gerhard MUller-Newen and Fred Schaper
SOCS proteins: negative regulators of the JAKISTAT pathway
Robyn Starr and Douglas J. Hilton
The PIAS protein family and TC-PTP Bin Liu and Ke Shuai
Prime time for the Drosophila JAKISTAT pathway Erika A. Bach and Norbert Perrimon
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xiii
1
11
27
43
55
75
87
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The STAT proteins of Dictyostelium Jeffrey G. Williams
JAKIST A Ts in zebrafish: conservation of JAKIST AT signaling in vertebrates
Andrew C. Oates and Leonard I. Zon
SECTION II MECHANISMS OF ACTIVATION OF AND TRANSCRIPTIONAL REGULATION BY
STAT PROTEINS
IFNs and STATs, an incestuous relationship Christian Schindler and Li Song
Mechanisms and biological roles of STAT activation by the IL-6 family of cytokines
Daisuke Kamimura and Toshio Hirano
Growth hormone induced activation and regulation of JAK2 and STAT proteins
Jason H. Kurzer and Christin Carter-Su
G protein-coupled-receptor mediated STAT activation Jose Miguel Rodriguez-Frade, Mario Mellado and Carlos Martinez-A.
Regulation of STATs by posttranslational modifications Thomas Decker, Mathias Muller and Pavel Kovarik
Interactions of STATs with SRC family kinases Corinne M. Silva, Julie L. Boerner and Sally J. Parsons
The role of phosphatases and reactive oxygen species in regulation of the JAKISTAT pathway
Andrew Lamer and Michael David
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123
137
155
177
191
207
223
237
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Raft-STAT signaling and transcytoplasmic trafficking Pravin B. Sehgal and Mehul Shah
Nuclear trafficking of STAT proteins Kevin M. McBride and Nancy C. Reich
Interaction of STAT signals with other signaling pathways
Duane R. Wesemann and Gerald M. Fuller
Forward genetics in mammalian cells Eugene S. Kandel and George R. Stark
X-ray crystal structure of STAT proteins and strnctnre-activity relationships
Christoph W. Muller, Montserrat Soler-Lopez, Christina Gewinner and Bernd Groner
STAT transcriptional activation mechanisms: communication with the basal transcriptional machinery
David E. Levy
STAT-dependent gene expression without tyrosine phosphorylation
Moitreyee Chatterjee-Kishore, Jinbo Yang and George R. Stark
SECTION III BIOLOGICAL IMPACT OF STAT ACTIVATION
JAKISTAT signaling: a tale of jeeps and trains Ana P. Costa-Pereira, Birgit Strobl, Bjorn F. Lillemeier, Hayaatun Is'harc and Ian Kerr
Viruses and STAT proteins: co-evolution with the JAK-STAT pathway
Christina M. Ulane and Curt M. Horvath
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343
355
367
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26. STATs in immune responses to viral infections 381 Christine A. Biron, Rachelle Salomon and Joan E. Durbin
27. IFNy receptor-ST ATl signaling and cancer 399 immunoediting
Ravindra Uppaluri, Gavin P. Dunn, Lloyd J. Old and Robert D. Schreiber
28. STAT activation in THlITH2 differentiation 419 Theresa L. Murphy and Kenneth M. Murphy
29. Mechanisms and biological consequences of STAT 435 signaling by cytokines that share the common cytokine receptor y chain, Yc
Jian-Xin Lin and Warren J. Leonard
30. STAT activation in the acute phase response 465 Heinz Baumann
31. STAT3 function in vivo 493 Valeria Poli and Tonino Alonzi
32. Tissue-specific function of STAT3 513 Kiyoshi Takeda and Shizuo Akira
33. Role ofSTATs in the biological functions of 525 growth hormone
Peter E. Lobie and David J. Waxman
34. STAT/SOCS family members in inflammation 545 and diseases
Akihiko Yoshimura, Ichiko Kinjyo, Kyoko Inagaki-Ohara and Toshikatsu Hanada
35. Signal Transducers and Activators of Transcription 559 in cytokine signaling
James N. Ihle
36. STAT signaling by erythropoietin 575 Stefan N. Constantinescu and Virginie Moucadel
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37. STATs in cell mobility and polarity during 595 morphogenetic movement
Susumu Yamashita and Toshio Hirano
38. Negative regulators of STAT function in Drosophila 609 Melissa A. Henriksen and Aurel Betz
39. Jak3 and the pathogenesis of severe combined 623 immunodeficiency
Fabio Candotti, Luigi Notarangelo, James A. Johnson, Daniel McVicar and John J. O'Shea
40. Constitutively active STATs and cellular 637 transformation
Tobias Dechow and Jacqueline Bromberg
41. STAT proteins as molecular targets for cancer therapy 645 RalfBuettner, Marcin Kortylewski, Drew Pardoll, Hua Yu and Richard Jove
42. STATs in the central nervous system 663 AzadBonni
43. STATs in the cardiovascular system 687 Hisao Hirota, Hideo Yasukawa and Kenneth R. Chien
44. JAKs and ST ATs as biomarkers of disease 697 Marisa Dolled-Filhart and David L. Rimm
45. Drug discovery approaches targeting the 721 JAKISTAT pathway
H. Martin Seidel and Jonathan Rosen
Author Index 743
Subject Index 745
COLOUR PLATES
gp130
~STAT JAK JAK
(l.'\)
Figure 1. The major steps of JAK-STAT signal transduction. (see p.4S)
xiii
XIV Colour Plates
Figure 2. Schematic representation of the IL-6-type cytokine receptor complex. The solved structures for viral IL-6/gp 130, gp80 and STAT3 (Brookhaven Databank accession numbers III R, I N26 and I BG I, respectively) are represented. (see p.46)
putative FERM domain
p-grasp domain
Colour Plates xv
kinase domain
JH1
Figure 3. Domain structure of Janus kinases and a structural model of the murine JAKI ~-grasp domain (aa 36-112) based on the solved structure of ubi quit in (taken from 28) (see p.49)
Upd
op (inactive)
y
Dome
o _ Hop
(aclive)
Phosphale ...... oy
Slal92
IA
Cytoplasm
Nucleus
Figure 1. The Drosophila JAKISTAT pathway (see p.SS)
XVI
A Goni.lbl.SI
)'!it cells
B
c
Colour Plates
Progeny or marked
lVild type gemllinc s.tem cell
Sperm
JAKISTAT activation Egrr activation
Progeny or marked
SlQl92!;-I-
/ Cell migmtion ...t1 .... ~ .nd morphogenesis
symclrical pre-p:lllcm NPsymmclry
Hub
Progeny or ectopic
O\'er-expression orupd
in the Hub
[] Posterior cells D Moin body rollicle ecHs D C.ntripodal cells o Stretched «Hs
Boroer cells • Polar cells
Figure 2. Roles of the JAKJSTAT pathway in spennatogenesis (A) and oogenesis (B, C). (see p.91)
Colour Plates XVII
A
c Immune responses
Complemcnl-like gene ~ Gram-positive bacteria Persephone scmmelwd s
Necrotic (PGRP)
? / ! .!6 Sl"'cttlc
________ ~*~----------~~~Oll ~ o Hop Pelle Tube o
'·0 oV SIBt92E
\ 00=1
1 ? 1
B Hematopoeisis
JAKISTAT I TolVNFKB
Immune
ch;)lIcngc
Uimelloc:),lC
Prohcmocytc
Proliferation! DifTerenli3.lion
Lz?
• • Cryslml cdr
PlumalOC)1t
Gram-negative ooclcria
?
± ImdlRlP
1 dTAKI
1 inlllDmlKKp KcnnyfDn, IKKy
1 Relish
\ Immune challenge \ Puparintion
M:Jcrophngc
Figure 3. Roles of the JAKISTAT pathway during hematopoiesis and innate immunity (see p.96)
XVIII Colour Plates
Figure 1. Mechanisms involved in GPCR dimerization. A. Coiled-coil motifs in the large C terminal domain are involved in GABA receptor heterodimerization. B. ~-adrenergic receptors dimerize through interactions between transmembrane a helices. C. Disulphide bonds between conserved cysteines in N-terminal regions contribute to glycoprotein receptor homodimerization. (see p.194)
Colour Plates XIX
Figure 1. Stat3 homodimer bound to its DNA target site. Depicted is the core domain of STA T3 (4) covalently linked to the N-domain (5). The dimer of the N-domain was created using the matrix given in (6). Figure adapted from (4). (see p.313)
Figure 2. DNA-binding of ST A T3 to one halfsite. Depicted are loops ab, ef and ga5 protruding from the Ig-fold domain. Asparagine 466 plays a central role in the recognition of base pairs 2, 3 and 4. Figures 2 and 3 reproduced from (4). (see p.315)
xx Colour Plates
Figure 3. View along the dyad which relates the two STAT monomers. The C-terminal phosphotyrosine peptide binds in trans to the other monomer. The disordered linkers between the end of the SH2 domain and the phosphotyrosine peptides are depicted in grey. (see p.316)
Figure 4. The transcriptional regulation exerted by STAT molecules might not be limited to induction of gene transcription. STAT molecules are able to interact with co-activators and corepressors, molecular complexes involved in transcriptional induction and transcriptional repression through the action of histone acetyltransferases and histone deacetylases. In analogy to nuclear honnone receptors (24), the association with positively or negatively acting regulatory components might be signal dependent. (see p.320)
Colour Plates xxi
Figure 5. STAT glycosylation by O-Iinked N-acetylglucosamine (O-GlcNAc) is a prerequisite for the interaction with the co-activator p3001CBP. Mutation of threonine 92 (acceptor of the sugar moiety) in STAT5 results in an induction deficient variant. (see p.322)
xxii Colour Plates
gp130 ..... IFNGRI
0V~ STATl STAT1
STATl
Figure I . JAKISTAT signaling in response to IL-6 and IFN-y. (see p .356)
Eg Eg B
Eg BY440 Eg BY90S
EpoR
gp130 ~ Box1 ~
I- F ;; K V683
=~ !440 Box2 -L( S V759 r-
~ J ~905
V767 K P V81 4
I- ] Stat1/3 activation p Q H 0
V90S ~ V V91S
Figure 2. Schematic representation of the Epo/gp 1 30-based chimeric receptors5.
(see p.358)
Colour Plates XXIII
Wu et al. Ceii 83 :5 9-67, 199.5
Soc olovsk.y et a]. Ce1198:181-191, 1999
Figure 1. Comparison of Embryos Deficient in Epo receptor or Stat5a!b with Wild Type Embryos. The pictures illustrate the reported appearance of Epo receptor deficient or Stat5alb deficient embryos at mid-gestation and compare them to wild type embryos. The sources of the original illustrations are indicated below the figures Top panel, left wild-type; right EpoR deficient. Bottom panel, left Stat5alb deficient, right wild-type. (see p.565)
XXIV Colour Plates
/
S ..
""', l'
~: :~~ ~~~1".T~ ~ ~, STAT .- STA.TIdNA.
1 ~ 'a: ~ STAT
MAna< t Y STAT ;r ~ ~j h mIIII ..... SUT{ ~~SCS_.~==A=~H=pq>OzI='===---,
] ,...tGt\lt BdX". I Caombulon /DproIfwdOl1
"":~ .... " .. ::t-,, ................. ............. /-.......... .. ...... ' .MY ••.
:,., ~ 'C S S S; s S;p;::;!e~S~ .... . .... \ ~ __ 6 /
...... .. .......... . ...... ....................................................... .......................
/ ~--..... -
Figure 1. Binding of Epo to the EpoR triggers the activation of JAK2 kinases, which phosphorylate themselves and tyrosine residues on the EpoR, providing docking sites for SH2 domain-containing signal transduction proteins. (see p.578)
Receptor Oligomerization --
MAP Kinase Pathway i L.lpld Signaling Other Pathways
STAT Serine Phosphorylalion p
(Transcriptional Activity
DNA
Cytokine·R •• ponsive Promoter Element
STAT Tyrosine Phosphorylation
I Cytoplasm I
Transcrlpllonallnductlon
"'" Allered Coil Phenotype
Figure 1. Activation of JAKs and ST ATs by cytokines. A schematic showing the steps involved in regulation of gene expression by cytokines through the JAKISTAT pathway. (see p.723)