The Protein Kinase Facts: Book. Protein-Serine Kinases

594 Pages·1995·15.409 MB·English

by  Grahame Hardie and Steven Hanks (Auth.)

Preface
The genesis of this book was in early 1991 when Susan King, then
commissioning editor of the new FactsBook series for Academic Press,
approached us individually with the idea of putting together a book on
protein kinases. Recognizing the enormity of the task, we each declined her
initial invitation to take sole responsibility for the project, but eventually
agreed to serve as co-editors. D.G.H.'s acquiescence probably arose from his
boredom due to an enforced restriction to an orthopaedic ward, while
recovering from a skiing accident in which both legs were broken!
Since 1987, S.K.H. has maintained a database of protein kinase catalytic
domain sequences which has proved useful for identifying conserved
features of primary structure, and as a tool for classification purposes. This
database served as the starting point for the book. Most of the information
in other volumes of the FactsBook series has been entirely compiled by the
academic editors, which has many advantages in terms of uniformity of
style. However, the protein kinase field is simply too immense for this to
be feasible, and a very early decision was made to enlist the help of
contributors who were experts in the study of the individual enzymes. Of
course this approach brought its own problems, related to the difficulty of
obtaining submissions from some 140 individuals by the agreed deadline.
At least one of the potential contributors we contacted did not reply for the
very understandable reason that he had died, while others had moved three
or four times since publishing their original paper on their protein kinase!
Then there was the problem of contributors interpreting the guidelines in
different ways, and providing their entries in different styles and formats.
This was by no means their fault, as the guidelines themselves evolved to a
certain extent as we gained experience.
Despite these inevitable difficulties, the majority of contributors were
enthusiastic about the project, and provided their entries on time and in
good shape, and we would like to express our gratitude to them all. They
made this book possible. Roger Perlmutter and Michael Jaye deserve special
thanks for agreeing to compile several important entries at the last minute.
Although editing the individual entries took several months, the
contributors had the opportunity to update their submissions shortly before
the book went to press, so the final versions should be reasonably up to
date. Because of restrictions on overall length necessary to maintain the
format of the Factsbook series, we very much regret that we were unable to
include most of the kinases published after April 1993, although these are
included in the Classification Table in the introductory chapter by SKH
and Tony Hunter.
Despite these attempts to keep the project down to a manageable size, a
rather late decision had to be taken to split the book into two volumes.
The only logical manner to do this seemed to be to include the protein-
serine/threonine kinases (including some which phosphorylate tyrosine on
there target proteins, e.g. Weel) in one volume, and the ''conventional"
protein-tyrosine kinase subfamily in the other. To allow each volume to
stand alone if necessary, the introductory chapters are reproduced in both,
plus a common index covering both volumes.
Finally, it is hard to conceive how this project could have been pulled off in
the days before floppy disks, FAX and electronic mail, and we feel the book is
a small testament to the power of modern communication. Given the
continued expansion of the number of defined protein kinases, electronic
methods of publication may also be necessary if future editions are to
become a complete resource. Whether the editors can also be replaced by
computer programs remains to be seen!
Left: Grahame Hardie, Right: Steven Hanks
Abbreviations
The list below only includes abbreviations which occur in more than one entry.
Abbreviations and acronyms for the protein kinases themselves are not included
in the list, but may be found in the index. Standard one- and three-letter abbre
viations for amino acids are used throughout the book.
A. thaliana Arabidopsis thaliana
bAR b-adrenergic receptor
BDNF brain derived neurotrophic factor
C subunit catalytic subunit
c- cellular (protooncogene) form of
C-terminal carboxyl-terminal
C. elegans Caenorhabditis elegans
CaM calmodulin
cAMP, cyclic AMP cyclic adenosine-3',5'-monophosphate
Cdk cyclin-dependent kinase
cDNA complementary DNA
cGMP, cychc GMP cyclic guanosine-3',5'-monophosphate
CNS central nervous system
CREB cAMP response element binding protein
CSF cytostatic factor
CSFl colony stimulating factor-1
D. discoideum Dictyostelium discoideum
D. melanogaster Drosophila melanogaster
DM myotonic dystrophy
dsRNA double stranded RNA
EGF epidermal growth factor
eIF2, eIF-2B eukaryotic initiation factor-2, -2B
EMS ethyl methane sulphonate
FGF-1, -n fibroblast growth factor-1, -n
G protein GTP-binding protein
G-CSF granulocyte-colony stimulating factor
GAP GTPase activating protein
GM-CSF granulocyte/macrophage-colony stimulating factor
HGF hepatocyte growth factor
HSV-1 herpes simplex virus type-1
IG50 concentration giving 50% inhibition
IFN-a, -b, -g interferon-a, -b, -g
Ig, IgM immunoglobulin, immunoglobulin-M
IGF-1, -2 insulin like growth factor-1, -2
IL-1, IL-n interleukin-1, interleukin-23
IRS-1 insulin receptor substrate-1
JHl, JH22 Jak homology-1, -n
kb kilobases
kDa kilodaltons
KL kit ligand
Abbreviations
MAP kinase mitogen-activated protein kinase
MCGF mast cell growth factor
MOL WT molecular weight
N-terminal amino-terminal
NGF nerve growth factor
NLS nuclear localization signal
NT-1, -n neurotrophin-1, -n
P-Tyr phosphotyrosine
P. falciparum Plasmodium falciparum
PCR polymerase chain reaction
PDGF platelet-derived growth factor
PDH pyruvate dehydrogenase
PH pleckstrin homology
pl isoelectric point
PI phosphatidyl inositol
PK protein kinase
PKI heat-stable protein inhibitor of cAMP-dependent protein
kinase
PLC, PLC-g phospholipase C, phospholipase C-g
PNS peripheral nervous system
PS pseudosubstrate site
PTK protein-tyrosine kinase
R subunit regulatory subunit
RFLP restriction fragment length polymorphism
S. cerevisiae Saccharomyces cerevisiae
S. pombe Schizosaccharomyces pombe
SCF stem cell factor
SDS-PAGE sodium dodecyl sulphate-polyacrylamide gel electro
phoresis
SF scatter factor
SHI, SH2, SH3 Src homology-1, -2, -3
SLF steel factor
T. parva Theileria parva
TCR T cell receptor
TGF-a, -b transforming growth factor-a, -b
TNF-a tumour necrosis factor-a
TPA 12-O-tetradecanoylphorbol 13-acetate
ts temperature sensitive
V- viral (oncogene) form of
X. laevis Xenopus laevis
1 Introduction
AIMS OF THE BOOK
Our aim in compiling this book was to provide a handy reference for people working
in the cell signalling field, so that basic information about a particular protein kinase
could be retrieved rapidly and with the minimum of searching in libraries and
databases. To keep the final purchase price reasonable, and to ensure a size and
general format in line with other volumes in the FactsBook series, the publishers
imposed a limit on overall length. This created particular difficulties for this
volume, since the protein kinases are now the largest known protein superfamily,
with the list of members still expanding at a remarkable rate.
The protein kinases we have included in the book were based on literature
searches compiled up to March 1993. We decided to restrict our list to those
which had been defined by sequencing of the catalytic subunit, with the exception
of a small number which were well defined biochemically but not cloned. In the
end, sequences appeared for most of the latter during production of the book, and
the only entry which does not have a sequence is EF2K. The March 1993 cutoff
was arbitrary, and we are well aware that a large number of new protein kinases
have appeared since then. It was unfortunately not possible to include them
because of the retrictions on overall length, and this is therefore one book which
is out of date even before it is published. We have tried to minimize this problem
in two ways. First, Table 1, Chapter 2 includes all protein kinases of which we
were aware at the time of going to press, although not all have entries in the book.
Secondly, although assembling and editing the entries took almost a year, all
contributors were given the opportunity to update their entries shortly before the
book went to press.
Having assembled a list in March 1993, the decision was taken to include only one
representative of each protein kinase from vertebrates, rather than having separate
entries for homologues from different vertebrate species. However due to the
importance of D. melanogaster, S. cerevisiae, S. pombe, C. elegans and D.
discoideum for genetic and developmental studies, we have included homologues
from those species even where the kinase was originally characterized in
vertebrates. We have also included, where available, one example from higher
plants, and a few protein kinases of general interest from other species (e.g. NimA
from Aspergillus nidulans). Applying these criteria was not always straightforward,
and with hindsight we know that one or two kinases that should have been
included were left out, while in one or two cases we have included as separate
entries what have turned out to be mere homologues. The contributor we
consulted for each entry was usually, but not always, the senior author from the
original sequence paper, and in the case of vertebrates the choice of which species
to discuss in detail was left up to him or her, although we had a slight preference
for the human sequence. From the references and database accession numbers
given, the reader should be able to find information on homologues in other species.
NOMENCLATURE
Nomenclature of protein kinases is a thorny and confused topic, with different
members of the superfamily being named either after their substrate(s), after their
regulatory molecules, after some aspect of the phenotype of a mutant, or by some
Introduction
arbitrary name or number. We hope that this book will be helpful to the uninitiated
in sorting out the morass of alternative names and acronyms. The conventions we
have used in naming the protein kinases are discussed below.
Acronyms
All protein kinases have been given an acronym, often derived from the gene name.
These acronyms are used to cross-reference protein kinases throughout the book,
using bold type. Thus "Xyz" in the text means that there is an entry for the
protein kinase ''Xyz'' elsewhere in the book. We have tried to use a consistent
style in devising acronyms, which has sometimes meant changing, with their
permission, those originally given by contributors. There is a widely accepted
convention that acronyms for genes are given in italics, whereas those for gene
products are in plain type. However, aside from that there appears to be little
conformity in the manner of presenting acronyms, even between researchers
working with different yeast species. Wherever possible we adopted the
convention now agreed for S. cerevisiae, in which gene names (wildtype) are given
in upper case and italics, whereas names of the corresponding gene products are
given in plain type with only the first letter in upper case. We did not feel that it
was necessary to add the suffix p to indicate the gene product. We have retained
the use of upper case throughout for some protein kinases which were well char
acterized biochemically before they were cloned, e.g. PKA or AMPK. Also, some
contributors working with C. elegans asked that we stick to the convention in
their research community, which is for the gene product to be in upper case
throughout, e.g. LET-23. Where protein kinases from different species would
otherwise have the same acronym, we have used prefixes to avoid confusion. Thus
vertebrate examples have no prefix, whereas examples from D. melanogaster, S.
cerevisiae, S. pombe, C. elegans, D. discoideum and higher plants have the
prefixes ''Dm'^ '^Sc'^ ''Sp'', ''Ce^', ''Dd'' and ''p", respectively. For example,
SpCdc2 refers to the originally described S. pombe gene product, whereas Cdc2
refers to the vertebrate homologue.
Full names
The original name given to a protein or gene at the time it was first isolated is not
always, with the benefit of hindsight, the best. Nevertheless researchers often
develop a strong emotional attachment to the name they coined, which they see as
being associated with the priority of their discovery. Although we tactfully
suggested to one or two contributors that they might change the name to one
which seemed less confusing to an outsider, in general the full name given is the
one chosen by the contributor. However all common alternative names are also
given below the full name. In one or two cases we have also given commonly used
alternative names when cross-referencing protein kinases, e.g. ''MAP kinase/Erkl/2''.
FINDING PROTEIN KINASE ENTRIES
Although we considered ordering entries alphabetically by acronym, we decided that
this would not necessarily be helpful due to the large variety of different names and
acronyms in use for a typical protein kinase. The entries have therefore been ordered
Introduction
into subfamilies defined by sequence relationships, using principles discussed in
Chapter 2. The quickest way to find the entry for a particular protein kinase is
likely to be the index, in which all acronyms and alternative names have been
listed. Protein kinases which do not have an entry, but are listed in Chapter 2,
also appear in the index, as do other genes or proteins which, although not
themselves protein kinases, are mentioned in entries.
ORGANIZATION OF THE DATA WITHIN AN ENTRY
Although the entries are hopefully self-explanatory, the format of a typical entry is
explained below. If any section!s) is (are) missing, either the information is not
known, or it was not provided by the contributor.
Introductory paragraph
This gives brief details on discovery and known functions.
Subunit structure and isoforms
This information is presented for each subunit and isoform as a table:
SUBUNIT AMINO ACIDS MOL WT SDS-PAGE
* •* •*• •••*
*Name of subunit or isoform.
**Number of amino acids in open reading frame.
***Calculated molecular weight of open reading frame (i.e. ignoring processing).
* * * * Apparent molecular weight of mature product on SDS-PAGE.
Information on quartemary structure is also given where known.
Genetics
Chromosomal locations and brief details of mutant forms are given.
Domain structures
With the exception of a few protein kinases which have a catalytic domain only,
diagrams of domain structure are included. These have been drawn to a uniform
format. With a few exceptions, the same scale was used, but the scale is always
given in any case. Although the domains are labelled, a key to the hatch patterns
used to denote various types of domain (e.g. kinase, SH2) is shown in Fig. 1.
Locations of known physiological phosphorylation sites are also marked.
Database accession numbers
A table of accession numbers for the PIR, SWISSPROT and EMBL/GENBANK
databases is given, including those for homologues whose sequence may not be
presented in the book.
Introduction
kinase
200 400 600 800 1000
CaM- Ca2+ EGF SH2 SH3 pleckstrin
binding (PKC) homology domain domain inomology
Fibro- Ig- Cys- cyclic cadherin signal
nectin III like rich nucleotide repeat sequence
Tzzm
CR1 Raf CR2 Raf DNA- GTP-GDP GAP kinase
homology homology binding exchange domain (Bcr)
Jak Jak Jak Jak Jak kinase-
homo- homo- homo- homo- homo- related
logy 3 logy 4 logy 5 logy 6 logy 7 (Jak)
^^n^^l ^1 ^1 ^ — ^M
auto- other
cyclin inhibitory Pro- Dimer- specified
box region rich ization domain
Figure 1: General format of domain diagram (Top), and key to hatch patterns used
to represent different types of domain (Bottom).
Amino acid sequences
Sequences of catalytic and regulatory subunits, including isoforms, from a single
species. Sequences are presented in single letter code with 50 residues per line.
Residues are generally numbered from the initiating methionine, but in certain
cases where this has been the previous practice, numbering is from the N-
terminus of the mature processed protein. Residues of interest (e.g. sites of
covalent modification, transmembrane domains) are underlined, and brief details
given after the sequence. Phosphorylation sites are double underlined.
Homologues in other species
Brief details of known homologues or related sequences in other species are given.
Physiological substrates and specificity determinants
This gives a description of physiological substrates, where known, or artificial
substrates used for assay. Description of consensus recognition sequence and
tables of sequences around known sites are also included.
Introduction
Assay
Brief details of enzymatic kinase assay are given where available,- full details are
given in references.
Enzyme activators and inhibitors
This gives information on activators and inhibitors which can be used as
experimental probes.
Pattern of expression
Expression of mRNA and/or protein, both temporal and spatial (e.g. tissue
distribution) is given.
References
A limited set of references is listed, with key references highlighted in bold.
2 The Eukaryotic Protein
Kinase Superfamily
Steven K. Hanks and Tony Hunter (Vanderbilt University School of Medicine,
Nashville, USA, and The Salk Institute, San Diego, USA)
The largest known protein family is made up of protein kinases identified largely from
eukaryotic sources. (The term ''superfamily" will be used hereafter to distinguish this
broad collection of enzymes from smaller, more closely related subsets which have
been commonly referred to as ''families''.) These enzymes use the gamma
phosphate of ATP (or GTP) to generate phosphate monoesters utilizing protein
alcohol groups (on serine and threonine) and/or protein phenolic groups (on
tyrosine) as phosphate group acceptors. They are related by virtue of their
homologous "kinase domains" (also known as "catalytic domains") which consist
of ?^250-300 amino acid residues [reviewed in refs 1-3, and see below]. Over the
past 15 years or so, previously unrecognized members of the eukaryotic protein
kinase superfamily have been uncovered at an exponentially increasing rate, and
currently appear in the literature almost weekly. This pace of discovery can be
attributed to the development of molecular cloning and sequencing technologies
and, more recently, to the advent of the polymerase chain reaction (PCR) which
encouraged the use of homology-based cloning strategies. Consequently, at the time
of this writing (April 1994), over 175 different superfamily members (products of
distinct paralogous genes) had been recognized from mammalian sources alone! The
prediction made several years ago"^, that the mammalian genome contains about
one thousand protein kinase genes (roughly 1 % of all genes) would still appear to be
within reason.
In addition to mammals and other vertebrates, eukaryotic protein kinase
superfamily members have been identified and characterized from a wide range of
other animal phyla, as well as from plants, fungi and microorganisms. Hence, the
protein kinase progenitor gene can be traced back to a time prior to the evolutionary
separation of the major eukaryotic kingdoms. Studies on the budding and fission
yeasts, Saccharomyces cerevisiae and Schizosaccharomyces pombe, have been
particularly fruitful in the recognition of new protein kinases. In these genetically
tractable organisms, the powerful approach of mutant isolation and cloning by
complementation has netted dozens of protein kinase genes required for numerous
aspects of cell function. In many cases now, vertebrate counterparts have been
found for these, leading to a growing awareness that protein phosphorylation
pathways that regulate basic aspects of cell physiology have been maintained
throughout the course of eukaryotic evolution.
While the overwhelming majority of protein kinases identified from eukaryotic
sources belong to this superfamily, a small but growing number of such enzymes do
not qualify as superfamily members. Most of these are related to the prokaryotic
"protein-histidine kinase" family (see below). Included in this category are a putative
ethylene receptor encoded by the flowering plant ETRl gene^, the product of the
budding yeast SLNl gene^ thought to be involved in relaying nutrient information to
elements controlling cell growth and division, the mitochondrial branched-chain a-
ketoacid dehydrogenase kinase (BKDK), and the mitochondrial pyruvate dehy
drogenase kinase (PDK). In addition, the Bcr protein encoded by the breakpoint
cluster region gene involved in the Philadelphia chromosome translocation and the