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

v

vi

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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3.

4.

5.

6.

7.

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

vii

v

xiii

1

11

27

43

55

75

87

viii

8.

9.

10.

11.

12.

13.

14.

15.

16.

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

105

123

137

155

177

191

207

223

237

17.

18.

19.

20.

21.

22.

23.

24.

25.

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

IX

247

269

285

299

311

327

343

355

367

x

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

xi

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)