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MINIREVIEW
ERK and cell death: ERK location and T cell selection
Emma Teixeiro and Mark A. Daniels
Department of Molecular Microbiology and Immunology, Center for Cellular and Molecular Immunology, School of Medicine, University of
Missouri, Columbia, MO, USA
Introduction
The development of a healthy immune system depends
on the generation of a diverse pool of T cells capable
of providing protection against a broad range of
pathogens, while avoiding an autoimmune attack on
healthy tissue. T cells recognize specific peptide anti-
gens presented in the context of self-major histocom-
patibility complex (MHC) molecules through clonally
distributed T cell antigen receptors (TCRs) expressed
early during T cell ontogeny. The TCR is formed by
the random association of variable and constant
genetic elements. Although this process leads to the
production of a diverse pool of pathogen-specific T
cells, it also leads to the generation of T cells that are
either useless, due to an inability to recognize MHC,
or extremely dangerous, due to the potential for an
overt reaction against self. Therefore, it is essential
that T cell development includes a selection process by
which only the useful cells are instructed to mature
and the nonfunctional and potentially harmful T cells
are eliminated before they can fully develop.
The shaping of the T cell repertoire begins when
immature T cell precursors, called thymocytes, are
selected by the ability of their TCR to recognize self-
peptides presented by MHC (pMHC) on the various
populations of antigen-presenting cells present in the

thymus [1]. A ‘Goldilocks’ affinity model of selection
has been proposed to describe this process. T cells that
are unable to recognize self-peptide MHC undergo
Keywords
ERK; MAPK; T cell selection; TCR signaling;
thymocyte
Correspondence
M. A. Daniels, Department of Molecular
Microbiology and Immunology, Center for
Cellular and Molecular Immunology, M616
Medical Sciences Bldg, One Hospital Drive,
Columbia, MO 65212, USA
Fax: +573 882 4287
Tel: +573 884 1659
E-mail:
(Received 19 June 2009, revised 14 August
2009, accepted 26 August 2009)
doi:10.1111/j.1742-4658.2009.07368.x
The selection of functional T cells is mediated by interactions between the
T cell antigen receptor and self-peptide major histocompatibility complex
expressed on thymic epithelium. These interactions either lead to survival
and development or death. The T cell antigen receptor is an unusual recep-
tor able to signal multiple cell fates. The precise mechanism by which this
is achieved has been an area of intense research effort over the years. One
model proposes that the differential activation of mitogen-activated protein
kinase pathways contributes to this decision. Here, the role of extracellular
signal-regulated kinase in promoting or preventing apoptosis during thymic
selection is discussed.
Abbreviations
BIM, Bcl2 like 11; DAG, diacylglycerol; Egr, early growth response protein; ERK, extracellular signal-regulated kinase; ITAM, immunoreceptor

tyrosine-based activation motif; JNK, c-JunNH
2
-terminal kinase; LAT, linker for activation of T cells; MAPK, mitogen-activated protein kinase;
MHC, major histocompatibility complex; pERK, phospho-extracellular signal-regulated kinase; pJNK, phospho-c-JunNH
2
-terminal kinase; PLC,
phospholipase C; SLP-76, SH2 domain containing leukocyte protein of 76 kDa; SAP-1, SRF accessory protein 1 (ELK4); SOS, son of
sevenless; TCR, T cell antigen receptor.
30 FEBS Journal 277 (2010) 30–38 ª 2009 The Authors Journal compilation ª 2009 FEBS
apoptosis (death by neglect). Weak or intermediate
TCR ⁄ pMHC interactions induce positive selection and
lead to the survival, development and maturation of a
self-restricted, yet self-tolerant, T cell repertoire
(reviewed in [2]). TCRs that bind self-peptide MHC
with high affinity induce either anergy [3], receptor
editing [4], deviation into regulatory T cell lineage [5]
or clonal deletion (apoptosis), which collectively are
considered to be negative selection [6]. Clonal deletion
is thought to be the dominant form of negative selec-
tion. Although this model of selection is generally
accepted, the question remains as to how the TCR can
translate subtle changes in ligand binding parameters
to signal such distinct cell fates as survival ⁄ differentia-
tion and death. The goal then is to establish the point
where the TCR signals diverge, leading to the ultimate
fate of either life or death for the developing
thymocyte. A differential signaling model, where
different mitogen-activated protein kinase (MAPK)
signals lead to either positive or negative selection, has
begun to emerge (reviewed in [2,7,8]). MAPK signaling

is important for determining cell fate decisions in a
diverse number of organisms and cell types (reviewed
in [7,8]). In thymocytes, c-JunNH
2
-terminal kinase
(JNK) [9], p38 [10] and extracellular signal-regulated
kinase 5 (ERK5) [11] are MAPKs essential for
negative selection, but do not influence positive selec-
tion. The small GTPase Ras initiates the MAPK cas-
cade that leads to Raf1–MEK1 ⁄ 2–ERK1 ⁄ 2 activation.
The phosphorylation of ERK1 ⁄ 2 is important for
positive selection and dispensable for negative selection
[12–15]. Interestingly, positive and negative selecting
ligands activate all four of these pathways. The conun-
drum is how does a T cell integrate these signals to
distinguish positive from negative selection? One possi-
ble explanation may be the location of the active form
of these signaling molecules within a cell. It was
recently shown, that in thymocytes, positive and nega-
tive selecting ligands induce the localization of the
components of the Ras ⁄ ERK cascade and active ERK
into distinct subcellular compartments (Figs 1 and 2)
[16]. Several groups have demonstrated that the biolog-
ical outcome of Ras ⁄ MAPK activation is determined
by its subcellular localization [8,17]. The role of ERK
in promoting or preventing clonal deletion (apoptosis)
during the thymic selection decision-making process is
the subject of this review.
Is LAT the fork in the TCR signaling
road?

A long-time goal of immunologists is to establish
where signals emanating from the TCR diverge and
lead to such distinct cell fates as survival and death.
Much is known about the events that occur immedi-
ately upon TCR engagement of pMHC. Lck is acti-
vated by CD45 and recruited to the TCR ⁄ CD3
complex by the coreceptors CD4 or CD8. Lck then
Fig. 2. Localization of pattern Ras ⁄ MAPK signaling intermediates
during negative selection. The figure depicts the location of mole-
cules described in the text in the case of TCR engagement by a
negative selecting ligand. Note the separate location of pJNK and
pERK, and Ras-GRP1 ⁄ Grb2 ⁄ SOS ⁄ Ras ⁄ Raf at the plasma
membrane.
Fig. 1. Localization of pattern Ras ⁄ MAPK signaling intermediates
during positive selection. The figure depicts the location of mole-
cules described in the text in the case of TCR engagement by a
positive selecting ligand. Note the similar location of pJNK and
pERK, and Ras-GRP1 ⁄ Ras ⁄ Raf at the Golgi.
E. Teixeiro and M. A. Daniels ERK location and T cell selection
FEBS Journal 277 (2010) 30–38 ª 2009 The Authors Journal compilation ª 2009 FEBS 31
phosphorylates the immunoreceptor tyrosine-based
activation motifs (ITAMs) of the CD3 subunits and
TCRf. This allows for the recruitment of the kinase
Zap-70 to the TCR and induces its activation
(reviewed in [18]). The TCRf chain contains six
ITAMs. Initially, studies comparing variants of agonist
peptides suggested that qualitative differences in TCRf
phosphorylation of individual ITAMs contributed to
the selection decision. In these studies, weak ligands,
capable of inducing positive selection, generated the

p21 form of phopho-f. High-affinity ligands, capable
of inducing negative selection, generated p23-f [19,20].
More recently, the mutation of selected ITAMs and
studies on f-chain phosphorylation have provided
more support for a quantitative than a qualitative
TCRf phosphorylation model [21–23]. One study has
suggested that phosphorylation of a defined number of
CD3 ITAMs is required for each developmental step
in selection [23]. Another study showed that a gradual
decrease in TCR affinity correlates with a gradual
decrease in total TCRf phosphorylation. Interestingly,
in spite of the small change in total TCRf phosphory-
lation between ligands that lie on either side of the
boundary of selection, the recruitment of active Zap-
70 to the membrane is markedly enhanced for negative
selecting ligands [16].
The TCR f chain does not have the capacity to
recruit a wide variety of signaling molecules [24]. How-
ever, one of the downstream targets of active Zap-70,
the linker for activation of T cells (LAT), contains
nine phosphorylatable tyrosines that are able to specifi-
cally recruit several signaling molecules essential for
thymocyte selection (reviewed in [25]). This suggests
that LAT could be a more suitable candidate as a
branch point in TCR signal transduction. Mutational
analyses specifically determined that the four distal
LAT tyrosines are critically important for T cell devel-
opment [26]. Phosphorylation of these tyrosines facili-
tates the recruitment of phospholipase C (PLC)c1,
Gads, SLP-76 and Grb-2. PLCc1 is essential for the

mobilization of calcium. The role of calcium, upstream
of calcineurin, has long been appreciated as being
important for thymocyte selection [27]. Activation of
PLCc1 also induces the generation of diacylglycerol
(DAG), which is essential for the activation of protein
kinase C-h and the guanine exchange factor Ras-
GRP1. Protein kinase C-h and Ras-GRP1 are impor-
tant for the activation of Ras ⁄ Raf1 ⁄ ERK and have
also been linked to positive selection in thymocytes
[28,29]. Ras-GRP1, on the other hand, appears to be
much less important for negative selection [30]. Gads
mediates the association of SLP-76, another Zap-70
substrate, to LAT. Mice deficient in Gads or SLP-76
are largely defective for positive and negative selection
[31,32]. Members of the Tec family of kinases associate
with LAT ⁄ Gads ⁄ SLP-76 and contribute to the stability
of the complex and enhance the activation of PLCc1.
Tec kinase deficiency alters both positive and negative
selection [33,34].
Grb2 is the only adaptor molecule recruited to LAT
that is uniquely required for negative selection. Its
ability to associate with the guanine exchange factor
son of sevenless (SOS) in T cells makes it an important
activator of the Ras ⁄ Raf ⁄ ERK pathway. Grb2 haploid
insufficient mice demonstrate decreased induction of
active JNK and p38 with a concomitant reduction in
negative selection. Interestingly, these mice do not
have a defect in the generation of phospho-ERK
(pERK) [35]. Together with the role of Ras-GRP1 in
ERK activation and positive selection, these data sug-

gest that negative selecting ligands would exclusively
activate Grb2 ⁄ SOS and positive selectors would acti-
vate Ras-GRP1. In support of this, positive selectors
do not recruit Grb2 ⁄ SOS to LAT. They only activate
Ras-GRP1 and induce its recruitment to the Golgi
[16]. However, the fact that negative selecting ligands
activate and recruit both Ras-GRP1 and Grb2 ⁄ SOS to
the plasma membrane argues against this. Mathemati-
cal modeling of LAT phosphorylation [36] and studies
on the phosphorylation kinetics of individual LAT ty-
rosines [37], indicate that the lack of Grb2–LAT inter-
action during positive selection may be due to partial
phosphorylation of LAT. In line with this, positive
and negative selecting ligands show quantitative differ-
ences in total phosphorylation of LAT [16], although
the phosphorylation state of individual tyrosines in
thymocytes has not been assessed. Taken together
these data favor a model where the signal emanating
from the TCR begins to diverge at LAT.
The location of ERK1
⁄
2 and selection
outcome
The differential recruitment of signaling intermediates
to LAT appears to have a direct consequence on the
regulation of downstream signaling pathways that are
important for determining the selection decision. One
of these is the Ras ⁄ ERK pathway. The role of the
Ras ⁄ ERK cascade in thymic selection has been well
studied (reviewed in [7]). Phosphorylation of ERK1 ⁄ 2

is essential for positive selection, but their role in nega-
tive selection is dispensable [12–15]. The activation of
ERK is linked to LAT through PLCc1 ⁄ DAG ⁄ Ras-
GRP1 ⁄ Ras and Grb2⁄ SOS ⁄ Ras (reviewed in [8]).
When thymocytes are stimulated by negative selecting
ligands, they induce a rapid, robust, yet transient
ERK location and T cell selection E. Teixeiro and M. A. Daniels
32 FEBS Journal 277 (2010) 30–38 ª 2009 The Authors Journal compilation ª 2009 FEBS
induction of pERK that is localized to the plasma
membrane (Fig. 2). On the other hand, positive select-
ing ligands induce a slow and sustained activation of
ERK originating from the Golgi and leading to pERK
being distributed throughout the cell (Fig. 1)
[16,38,39]. The differences in the kinetics of pERK
induction may be explained by both the location and
the identity of the upstream activators of Ras. Ras
activation by only Ras-GRP1 follows a graded
response that correlates with the stimulus, whereas
SOS, on the other hand, contains a positive feedback
loop that dramatically increases the rate of Ras activa-
tion [40]. Furthermore, there is a marked increase in
negative regulation of Ras at the plasma membrane
versus the Golgi [8]. Therefore, the differential recruit-
ment of Grb2 ⁄ SOS and Ras compartmentalization
describe a potential mechanism for the differences in
pERK kinetics observed between positive and negative
selecting ligands [16,38,39].
The method that thymocytes utilize for the compart-
mentalization of the components of the Ras ⁄ ERK
pathway is not completely understood. The regulation

of activation and membrane recruitment of Ras-GRP1
is dependent on calcium and DAG. One could imagine
a scenario where the slow generation of calcium (and
DAG) induced by positive selectors activates Ras-
GRP1, which then binds to the DAG-rich Golgi [8,16].
Conversely, the robust calcium flux induced by nega-
tive selectors could correlate with the generation of
large quantities of DAG at the plasma membrane and
lead to Ras-GRP1 recruitment to that location. Recent
work has demonstrated that in T cells, PLCc1 activa-
tion leads to activation of Ras-GRP1 and its recruit-
ment to the Golgi and lymphocyte function-associated
antigen (LFA-1)-mediated activation of phopholipase
D2 leads to activation of Ras-GRP1 on both the Golgi
and the plasma membrane [41]. In addition, DAG kin-
ases have also been shown to play an important role
in the regulation of Ras-GRP1 localization [42,43].
The location of Ras-GRP1 and SOS in turn lead to
the recruitment, activation and compartmentalization
of Ras to the different membranes within a cell.
Downstream of Ras, various MAPK scaffolds that are
restricted to different membrane compartments are
probably responsible for the localization of pERK [8].
One such scaffold, kinase suppressor of Ras (KSR)1,
has been shown to be important for the membrane
localization of ERK and to somehow play a role in T
cell development [44,45]. How these processes combine
to determine the localization pattern of Ras ⁄ ERK in
thymocytes remains to be seen. The classic paradigm
of ERK activation would predict that once phosphory-

lated, ERK dissociates from the scaffold where it can
either act on cytosolic targets or move to the nucleus
to activate transcription factors (reviewed in [7,8]). In
light of this, the localization of pERK at the plasma
membrane by negative selecting ligands is most curious
(Fig. 2). Whether it is somehow sequestered at the
plasma membrane or subject to rapid dephosphoryla-
tion is a question that remains to be answered. When
all of this is considered together, differences in the
location of pERK may provide the developing thymo-
cyte with the ability to distinguish positive and nega-
tive selecting ligands. Although the precise mechanism
of how differential MAPK compartmentalization con-
tributes to this decision is open to debate, possible
implications of pERK localization are discussed below.
Several transcription factors that are downstream
targets of ERK1 ⁄ 2 play an important role in mediating
positive selection. SRF accessory protein 1 (ELK4)
(SAP-1) is a ternary complex factor subfamily member
of Ets transcription factors that is activated by
pERK1 ⁄ 2. Deficiency of SAP-1 leads to a block in
positive selection [46]. Activation of SAP-1 leads to the
expression of early growth response protein (Egr)1.
Overexpression of Egr1 results in positive selection on
a nonselecting background [47], and Egr1-deficient
mice are impaired for positive selection [48]. ERK1 ⁄ 2
activation also leads to a reduction in DNA binding
by the basic helix–loop–helix protein E2A through the
increased expression of the inhibitor of basic helix–
loop–helix protein Id3 [49]. E2A-deficient mice have

enhanced positive selection [50]; Id3-deficient mice
demonstrate a profound block in positive selection
[51]. Therefore, the sequestration of active ERK at the
plasma membrane by negative selectors may effectively
block the activation of these nucleus-resident transcrip-
tion factors tipping the balance in favor of negative
selection.
Active ERK1 ⁄ 2 may also contribute to thymic selec-
tion by regulating the balance of proapoptotic and
prosurvival proteins in the cytosol (reviewed in [52]).
Apoptosis induced by negative selection does not
involve classical death receptor pathways, rather it
depends (at least in part) on the nuclear orphan steroid
receptor Nur77 (discussed later) and the proapoptotic
BH3-only Bcl-2 family member Bcl2 like 11 (BIM).
The prosurvival molecules Bcl-2 and Bcl-x
L
are able to
bind and sequester the proapoptotic molecules Bax
and Bak to prevent them from inducing apoptosis.
Once active, BIM is able to bind Bcl-2 or Bcl-x
L
, lead-
ing to the release and activation of Bax ⁄ Bak and apop-
tosis [53]. Thymocytes from male mice lacking Bim are
severely impaired for negative selection of the auto-
reactive male antigen specific HY-TCR [54]. In addi-
tion, the defect in negative selection in the nonobese
E. Teixeiro and M. A. Daniels ERK location and T cell selection
FEBS Journal 277 (2010) 30–38 ª 2009 The Authors Journal compilation ª 2009 FEBS 33

diabetic mouse strain has been linked to defective
induction of BIM, among other proapototic molecules,
enhancing its importance for negative selection [55,56].
Post-translational modifications can affect both the
level of expression and the proapoptotic activity of
BIM. For example, ERK-mediated phosphorylation of
BIM can target it for ubiquitination and degradation
(reviewed in [52,57]) or inhibit its proapoptotic activity
by reducing its binding to the prosurvival molecules
Mcl-1 and Bcl-x
L
[58,59]. Interestingly, JNK phospho-
rylates BIM on the same residue as ERK. However,
JNK also recruits the prolyl-isomerase Pin1 and
induces a conformational change in BIM that enhances
its proapoptotic potency in neuronal cells [60]. JNK
has also been implicated in the upregulation of BIM
expression [52] and JNK-mediated phosphorylation of
BIM facilitates its release from sequestration by dynein
motor complex [61]. Whether these findings hold true
in developing thymocytes is not known. During nega-
tive selection, whether BIM is regulated through tran-
scription, post-translational modification or both
remains to be determined. In summary, although BIM
is recognized to be critically important for negative
selection, the mechanism of its regulation is still
unclear.
Negative selecting ligands induce a rapid and robust
induction of phopho-ERK1 ⁄ 2, whereas positive select-
ing ligands induce slow and sustained activation of

pERK1 ⁄ 2 [38,39]. These data suggest the possibility of
a kinetic discrimination model for thymic selection.
However, this cannot explain how strong induction of
pERK1 ⁄ 2 by negative selectors does not rescue the
thymocyte from apoptosis, especially in the light of the
roles of pERK1 ⁄ 2 just described. Consider then, active
JNK is distributed throughout the cell and has the
same kinetics regardless of ligand strength [16,39]. Fur-
thermore, positive selecting ligands induce pERK1 ⁄ 2
throughout the cell similar to phospho-JNK (pJNK).
By contrast, negative selecting ligands lead to the acti-
vation and retention of pERK at the plasma mem-
brane. The net result is that negative selectors induce
segregation of pERK1 ⁄ 2 and pJNK [16]. This suggests
that the localization of pERK1 ⁄ 2 determines the selec-
tion outcome. Along this line, targeting of the Raf ⁄
MEK ⁄ ERK MAPK module to either the cytoplasm or
the plasma membrane in a neuronal cell line leads to
switch-like differences in biological outcome [62].
Additionally, studies from several groups have demon-
strated that the subcellular localization pattern of
Ras ⁄ MAPK determines the signaling output in a vari-
ety of cell types (reviewed in [8]). Given the competing
roles of ERK1 ⁄ 2 and JNK in determining selection,
these data suggest that retention of pERK1 ⁄ 2 at the
plasma membrane mimics the effect of an ERK knock-
out and gives pJNK an unopposed opportunity or at
least a head start in activating the proapoptotic effec-
tor molecules necessary for negative selection. Alterna-
tively, a model where a unique signal is provided by

membrane-bound pERK cannot be ruled out. Regard-
less, it is attractive to hypothesize that the differential
compartmentalization of Ras ⁄ ERK pathways provides
the thymocyte with the ability to distinguish between
positive and negative selecting ligands [16]. Future
studies are needed to establish whether the localization
pattern is sufficient to determine selection outcome.
ERK5, Nur77 and negative selection
The orphan steroid receptor Nur77 is part of a small
family of transcription factors (which also includes
Nurr1 and Nor1) that is thought to play an important
role in mediating TCR-induced apoptosis in immature
thymocytes. It acts in a pathway that is not redundant,
but rather parallel to BIM (reviewed in [52]). The
importance of Nur77 as a proapoptotic molecule in T
cells was first described in hybridomas [63,64]. Using
various models of negative selection, dominant nega-
tive Nur77 resulted in a decrease in negative selection,
whereas constitutively active mutants led to an increase
in negative selection [65,66]. However, Nur77-deficient
mice do not have a defect in negative selection. This
apparent discrepancy can be explained by considering
the redundant role of the related family member Nor1
in mediating clonal deletion and the fact that the dom-
inant negative form of Nur77 is able to inhibit the
function of the other family members and block dele-
tion of autoreactive thymocytes [67].
Upon TCR stimulation, Nur77 transcription is
upregulated through the ERK5 ⁄ MEF2 pathway
[11,68,69]. The activation of Nur77 occurs by a cal-

cium-dependent pathway that ultimately leads to its
phosphorylation by ERK5 [70,71]. On the other
hand, Akt-mediated phosphorylation of Nur77 inhib-
its its DNA-binding activity [72], and there is specula-
tion that ERK2 phophorylation can also inhibit
Nur77 function by phosphorylation on a site distinct
from the ERK5 target site [73]. Given these and
other roles of Akt and ERK2 [15], these data suggest
an additional mechanism by which thymocytes could
distinguish positive from negative selecting ligands.
The mechanism by which Nur77 mediates the induc-
tion of apoptosis is less clear. Transcriptional activity
correlates with apoptosis in Nur77 transgenic thymo-
cytes and Nur77-deficient mice [70,74]. In fact, Nur77
induces the proapoptotic gene Nur77 downstream
gene 1 ( NDG1), FasL and TNF-related apoptosis-
ERK location and T cell selection E. Teixeiro and M. A. Daniels
34 FEBS Journal 277 (2010) 30–38 ª 2009 The Authors Journal compilation ª 2009 FEBS
inducing ligand (TRAIL) [75], but the physiological
relevance of some of these molecules in clonal dele-
tion of thymocytes has not been tested. Other studies
have shown that Nur77 can translocate from the
nucleus to the mitochondria, where it binds to Bcl-2,
converting it from a prosurvival factor into a proapo-
totic molecule [76–78]. A conflicting study reported
that efficient export of Nur77 was only observed in
mature T cells and immature thymocytes did not
translocate Nur77 to the cytosol [79]. The observed
differences, which could be due to the type of cell
examined, experimental technique, model system or

maturation state of thymocytes tested, need to be
resolved to make an accurate conclusion. Further-
more, although these two models of Nur77-induced
apoptosis are not necessarily mutually exclusive, it is
difficult to reconcile the mitochondrial data with the
correlation between transcriptional activity and apop-
tosis [52]. Interestingly, the activation of ERK5, dis-
pensable for positive selection, has a kinetic level of
induction that is similar between positive and negative
selecting ligands [11]. This resembles what has been
reported for JNK and p38 [39] and again suggests
that sequestration of pERK at the plasma membrane
by negative selecting ligands may be necessary for the
induction of signals necessary for negative selection.
Conclusions
Understanding the mechanisms that determine central
tolerance is essential to the regulation of autoimmuni-
ty, infectious disease and cancer. The mechanism by
which T cells translate the parameters of ligand
engagement into positive or negative selection has been
elusive. The default for a preselection double-positive
thymocyte is death. The time involved to complete the
selection process and the requirement for intact thymic
architecture have made studying the process of nega-
tive selection extremely difficult. In spite of this, MAP-
Ks, ERK1 ⁄ 2, ERK5, JNK and p38, are known to be
involved in the induction of positive versus negative
selection in the thymus. ERK5, JNK and p38 are
required for negative selection and dispensable for
positive selection. On the other hand, ERK1 ⁄ 2 is only

involved in positive selection. At first glance, this
appears to describe the mechanism of selection. Yet,
the fact remains that these molecules are activated by
both positive and negative selecting ligands. Differen-
tial subcellular localization of these, and possibly other
signaling intermediates, provides the developing
thymocyte with the tools to overcome this apparent
problem. Interestingly, JNK activity and subcellular
location are the same regardless of the ligand strength,
whereas ERK activity and location change depending
of the nature of the selecting ligand. In addition, the
kinetics of the other MAPK important for negative
selection are the same independent of the ligand. Given
their opposing function and downstream targets, this
appears to give ERK a prominent role in determining
the outcome of thymic selection. Further studies are
needed to demonstrate how ERK and JNK compete
and if location is sufficient to determine selection out-
come.
Acknowledgements
We would like to thank Dr Bumsuk Hahm and Dr
Mark McIntosh for critical reading of the manuscript
and Dr Ed Palmer for his support. Work from the
laboratory of MAD and ET are supported by the
University of Missouri Mission Enhancement Fund.
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