An essential role of pak1 phosphorylatio

Oncogene (2005) 24, 4591–4596

& 2005 Nature Publishing Group All rights reserved 0950-9232/05 $30.00
www.nature.com/onc

An essential role of Pak1 phosphorylation of SHARP in Notch signaling
Ratna K Vadlamudi1, Bramanandam Manavathi1,2, Rajesh R Singh1,2, Diep Nguyen1, Feng Li1
and Rakesh Kumar*,1
1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard,
Houston, TX 77030, USA

The p21-activated kinases (Paks), an evolutionarily
conserved family of serine/threonine kinases, play an
important role in cytoskeletal reorganization in mammalian cells. The Notch signaling pathway plays an important
role in the determination of cell fate/differentiation in a
number of organs. Notch signaling is a complex process,
and the mechanism by which Notch regulates multiple
cellular processes is intriguing. The expression of both
Notch and Pak1 has been shown to be deregulated in
several human cancers. Using yeast two-hybrid screening,
we identified SHARP, one of the Notch signaling
components, as a Pak1-interacting protein. We found
that SHARP is a physiologic interacting substrate of
Pak1, and that this interaction enhances SHARPmediated repression of Notch target genes. Pak1 phosphorylation sites in SHARP were mapped to Ser3486 and
Thr3568 within the SHARP repression domain. Mutation
of Pak1 phosphorylation sites in SHARP, inhibition of
Pak1 functions by a Pak1-autoinhibitory fragment (amino
acids 83–149), or expression of Pak1-specific siRNA
interfered with SHARP-mediated repression of Notch
target reporter gene activation. These results demonstrate

that Pak1–SHARP interaction plays an essential role in
enhancing the corepressor functions of SHARP, thereby
modulating Notch signaling in human cancer cells.
Oncogene (2005) 24, 4591–4596. doi:10.1038/sj.onc.1208672
Published online 11 April 2005
Keywords: Pak1 signaling; SHARP; Notch; repression

The Notch signaling pathway plays an important role in
the determination of cell fate (Schweisguth, 2004), and
influences cell proliferation, differentiation, and apoptosis in a variety of cell types (Miele and Osborne, 1999).
Initial studies with Notch signaling components suggested its involvement in neurogenesis (Beatus and
Lendahl, 1998), but subsequent work showed its
involvement in most organs (Iso et al., 2003). Binding
of specific ligand to Notch receptors triggers cleavage of
the transmembrane receptor, giving rise to the Notch
intracellular domain, which translocates to the nuclear
*Correspondence: R Kumar; E-mail:
2
Both these authors contributed equally to this work
Received 10 September 2004; revised 7 February 2005; accepted 11
February 2005; published online 11 April 2005

compartment, interacts with transcription factor RBPJk, and activates transcription of Notch target genes
such as HES (Hairy enhancer of Split) (Iso et al., 2003).
In the absence of Notch intracellular interaction, RBPJk acts as a corepressor of Notch target genes by
recruiting corepressors, including SMRT/NCOR and
HDACs (Kao et al., 1998; Hsieh et al., 1999; Zhou and
Hayward, 2001). Recent studies have identified SHARP
as novel component of the Notch-RBP-Jk signaling
pathway and implicated SHARP in repressing Notch

target genes in the absence of activated Notch (Oswald
et al., 2002). The molecular mechanisms by which Notch
promotes RBP-Jk activation and the pathways that
enhance RBP-Jk repression are not clear at the moment
and are an area of active investigation.
The p21-activated kinase 1 (Pak1), an evolutionarily
conserved family of serine/threonine kinase, was initially
identified as effectors of the Rho family of GTPases
(Bokoch, 2003; Vadlamudi and Kumar, 2003). Pak1 was
initially identified in the rat brain as a serine/threonine
kinase activated by Rac1 or Cdc42 (Manser et al., 1994).
Pak1 has been shown to play an important role in a wide
variety of functions, including cytoskeletal reorganization and cell survival (Vadlamudi and Kumar, 2003).
Evidence also exists that Pak1 has an essential role in the
dendrite formation and neurite outgrowth (Daniels
et al., 1998; Hayashi et al., 2002). Emerging data
indicate that Pak1 phosphorylates histone H3 (Li
et al., 2002), undergoes phosphorylation during mitosis
(Thiel et al., 2002), and localizes to the nuclear
compartment suggesting that Pak1 also plays an
important role in nuclear signaling. In the present study,
we used yeast two-hybrid screening of a mammary gland
cDNA library to identify SHARP, one of the Notch
signaling components, as a Pak1-interacting protein.
To confirm this SHARP and Pak1 interaction, we
cotransfected purified SHARP and Pak1 cDNAs into a
yeast strain that stably expresses nutrient reporter
genes. Yeast transformed with both Pak1 and SHARP
but not with either one alone showed the ability to
grow on medium that selects for one-on-one protein–

protein interactions (Figure 1a), confirming our initial
yeast two-hybrid screen results. To show the in vivo
interaction of Pak1 and SHARP, we cotransfected
a T7-tagged C-terminal SHARP fragment and myctagged Pak1 into 293 cells. Immunoprecipitation of
T7-tagged SHARP revealed the presence of Pak1 in
the precipitates (Figure 1b, left panel). Similarly,


Role of Pak1 phosphorylation in Notch signaling
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Figure 1 Identification of SHARP as a Pak1-binding protein. (a) Yeast cells were cotransfected with GAD-SHARP and GBD vector,
or GBD-Pak1 N-ter (aa 1–270), or GBD-Pak1 C-ter (aa 270–545). Cotransformants were plated on selection plates lacking leucine and
tryptophan (LT) or adenosine, histidine, leucine, and tryptophan (AHLT). Growth was recorded after 72 h. Growth on AHLT plates
indicates protein–protein interaction between SHARP and Pak1. (b) In vivo interaction of Pak1 with SHARP. HEK 293 cells were
cotransfected with myc-tagged Pak1 and T7-tagged SHARP C-terminal regions (aa 3281–3661) and cell lysates were
immunoprecipitated with control IgG, myc, or T7 epitope tag antibody. The presence of Pak1 and SHARP in the precipitates was
analysed by Western blotting. (c) Pak1 and SHARP interaction in the GST pull-down assays. SHARP (aa 3281–3661) was translated in
vitro using a transcription and translation system (Promega), and 35S-labeled SHARP was incubated with either GST-Pak1 or GSTPak1 deletions. Binding was analysed by GST pull-down assays followed by sodium dodecyl sulfate–polyacrylamide gel electrophoresis
(SDS–PAGE) and autoradiography

immunoprecipitation of myc-Pak1 with an mycepitope antibody also co-immunoprecipitated SHARP
(Figure 1b, right panel), demonstrating protein–protein
interaction between Pak1 and SHARP in vivo. Moreover, GST-Pak1 efficiently interacted with SHARP in
the GST pull-down assays (Figure 1c). Using serial
deletions of Pak1, we next identified the segment of
Pak1 comprising amino acids (aa) 75–132 as the
SHARP binding site (Figure 1c). Collectively, these

results provide evidence that Pak1 interacts with
SHARP both in vitro and in vivo.
Since Pak1 is a serine/threonine kinase, we next
examined whether SHARP is a substrate of Pak1. An in
vitro kinase assay using purified GST-SHARP and Pak1
enzyme showed that Pak1 could phosphorylate SHARP
(Figure 2a). Further, SHARP deletion analysis determined that Pak1 phosphorylation sites were localized in
the C-terminus of SHARP (aa 3471–3661, Figure 2b).
This region of SHARP contains two potential Pak1
consensus sites, serine 3486 and threonine 3568. Singlepoint mutation of either serine 3486 or threonine 3568 to
alanine partially reduced Pak1 phosphorylation of
SHARP (Figure 2c, lanes 2 and 3, respectively). Double
mutation of both serine and threonine to alanine
completely abolished SHARP phosphorylation in vitro
(Figure 2c, lane 4). To demonstrate phosphorylation of
SHARP in vivo, we used metabolic labeling of 293 cells
with [32P]orthophosphoric acid and transient transfection of the C-terminal SHARP, which contained both
Pak1 phosphorylation and binding sites. Immunoprecipitation of T7-SHARP from the cells showed that
SHARP is indeed a phosphoprotein (Figure 2d). MutaOncogene

tion of both Pak1 phosphorylation sites (Figure 2e) or
transfection of Pak1-siRNA substantially reduced the
phosphorylation status of SHARP (Figure 2f). We have
also observed some basal phosphorylation of SHARP,
which is not affected by mutation of Pak1 sites or
inhibition of Pak1 expression (Figure 2e and f, lower
band). These findings suggest that SHARP is phosphorylated by Pak1 under physiological conditions, and
that SHARP is an interacting substrate of Pak1.
Recent studies showed that SHARP is a novel
component of the Notch/RBO-Jk signaling pathway.

Since Pak1 is abundantly expressed in the neuronal
system (Manser et al., 1994), we examined whether Pak1
could modulate Notch/RBP-Jk signaling via its interactions with SHARP. To test this possibility, we used a
previously described and widely used transient cotransfection assay utilizing an RBP-Jk-responsive luciferase
reporter gene, which contains six repeats of EBNA2responsive element (pGa981/6-luc) and RBP fused VP16
(RBP-VP16) to enable readout of RBP recruitment to
the target promoters in 293 model cells (Oswald et al.,
2002). Cotransfection of RBP-VP16 activated the
reporter gene and SHARP repressed the activity of the
reporter gene, confirming the earlier reported finding
that SHARP represses Notch target genes (Oswald
et al., 2002). Interestingly, cotransfection of Pak1 along
with SHARP further enhanced the SHARP-mediated
repression, suggesting that Pak1 phosphorylation of
SHARP may promote its repression functions
(Figure 3a). To examine the possibility that Pak1
phosphorylation sites play an important role in SHARP
functions, we mutated both Pak1 phosphorylation sites


Role of Pak1 phosphorylation in Notch signaling
RK Vadlamudi et al

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Figure 2 SHARP is a substrate of Pak1. (a) In vitro Pak1 kinase reaction was performed using purified Pak1 enzyme and GST or GST
SHARP (aa 3281–3661) as a substrate as described elsewhere (Li et al., 2002). Phosphorylation of SHARP was analysed by SDS–
PAGE followed by autoradiography. (b) In vitro Pak1 kinase assay was performed by using various deletions of SHARP as a substrate.
(c) In vitro Pak1 kinase assay using wild-type or single or double mutants of SHARP proteins as substrates. (d) HEK 293 cells were
transfected with T7-SHARP and metabolically labeled with [32P]orthophosphoric acid. After 48 h, cell lysates were immunoprecipitated

with control IgG or T7 monoclonal antibody and the phosphorylation status of T7-SHARP was analysed by autoradiography. (e)
HEK 293 cells were transfected with wild-type or double mutant of SHARP (S3568AT3568A). After 48 h, cells were labeled with
[32P]orthophosphoric acid and the phosphorylation status was analysed by autoradiography. (f) HEK 293 cells were transfected with
T7-SHARP (aa 3281–3661) with or without Pak1 siRNA vector. Cells were metabolically labeled with [32P]orthophosphoric acid, and
after 48 h, the phosphorylation of T7-SHARP (aa 3281–3661) was analysed by autoradiography. (g) Schematic diagram showing the
localization of Pak1 phosphorylation sites in the SHARP repression domain

in the context of full-length SHARP (SHARP-S3486A,
T3568A). Cotransfection of SHARP or SHARPS3486A, T3568A substantially reduced the ability of
SHARP to reduce the reporter gene activity (Figure 3b).
Similarly, inhibition of endogenous Pak1 activity by
transfection of the Pak1-autoinhibitory domain (Pak1
aa 83–149) also reduced the SHARP-mediated repression of RBP-Jk-responsive reporter gene. These results
suggested that Pak1 phosphorylation modulates
SHARP repression functions.

To further examine the role of the Pak1–SHARP
interactions in Notch signaling, we used a dominant
active form of Notch (constitutively activated Notch
plasmid that lacks extracellular domain, Notch-1 del E).
HEK 293 cells were transiently transfected with wildtype SHARP or SHARP-S3486A, T3568A, along with
the RBP-Jk reporter gene. As expected, Notch-l del E
activated the RBP-Jk reporter gene, while coexpression
of wild-type SHARP inhibited the reporter gene activity
(Figure 4a). However, cotransfection of the SHARP
Oncogene


Role of Pak1 phosphorylation in Notch signaling
RK Vadlamudi et al

4594

a pGa981-6-Luc
VP16

RBP

Relative pGA981-6 luc activity

EBNA2
reselement
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0
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RBP-vp16
SHARP
Pak1 (ng)

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+
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+

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pGa981-6 luc

-

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RBP-vp16
Pak1
SHARP (WT)
SHARP (DMT)
Pak1 Inhibitor

Figure 3 Pak1 enhances SHARP-mediated repression. (a) Schematic representation of pGa9811/6 luc construct and RBP-VP16
activator used in the reporter gene assay. The reporter construct
contains four EBNA2 response elements, which are recognized by
RBP-Jk transcription factor. In the RBP-VP16 activator, RBP-Jk
was fused to the VP16 activation domain and thus acts as a
constitutive activator of RBP-Jk target genes. HEK 293 cells were
cotransfected with RBP-Jk reporter gene pGa981/6 luc (2 mg) and
RBP-VP16 (100 ng), with or without increasing amounts of
SHARP (100 and 200 ng) and Pak1 (100 ng) expression plasmids.
After 48 h, luciferase activity was determined by using a comertial
luciferase assay kit (Promega) and normalized to b-gal activity.
(b) HEK 293 cells were cotransfected with pGA981/6 luc and
RBP-VP16 together with SHARP wild type or mutant that lacks
Pak1 phosphorylation sites. When indicated, Pak1 wild type or Pak
inhibitor (Pak1 aa 83–149) was included in the cotransfection.
After 48 h, luciferase activity was measured and normalized to
b-gal activity

mutant, which lacks Pak1 phosphorylation sites, failed
to inhibit Notch-mediated activation of RBP-Jk
reporter gene (Figure 4a). Similarly, cotransfection of
Pak1-specific siRNA vector (Li et al., 2003), which
reduces Pak1 endogenous levels or Pak1-autoinhibitory
fragment (aa 83–149), also interfered with SHARP
Oncogene

repression of Notch-mediated transactivation of the
reporter gene (Figure 4b). Together, these findings
suggest that Pak1 phosphorylation of SHARP is
important for a productive repression of Notch target
genes by SHARP.
To further implicate the potential contribution of
Pak1 regulation of SHARP in exerting transcriptional
repressor activity of SHARP, we next examined the
effects of these regulatory interaction upon the transactivation function of Notch on Hes-1, an accepted
physiological target of Notch (Ohtsuka et al., 1999). In
this context, NIH3T3 murine fibroblast cells were
transfected with HES-1 promoter reporter, Notch-l del
E and either SHARP alone or combined with wild-type
Pak1 or Pak1-autoinhibitory domain expressing plasmids, and reporter activity was measured after 48 h
(Figure 4c). As expected from the previous work, Notch
del E activated the Hes-1 promoter-luc activity, while
SHARP coexpression resulted in a distinct reduction by
50% (Figure 4c). Interestingly, we also observed a
further significant repression of Hes-1 promoter-luc
activity when cells were cotransfected with Pak1,
whereas Pak1 inhibitor relieved the repression.

To validate the noted repression of Hes-1 promoter
activity by coexpression of SHARP and Pak1, we next
depleted the endogenous Pak1 using a Pak1-specific
siRNA in NIH3T3 cells, and examine the status of Hes1 mRNA by RT–PCR analysis. We found that a
reduced expression of Pak1 leads to a significant and
reproducible upregulation of Hes-1 mRNA as compared
to the cells transfected with the control siRNA (Figure 4d).
Together, these findings suggest that Pak1 signaling
indeed regulates the levels of Notch targets in vivo.
Phosphorylation-dependent signaling has been proposed as a potential mechanism for regulation of
deacetylase-catalysed transcriptional repression (Galasinski et al., 2002). Serine phosphorylation of SMART
by CK2 (Zhou et al., 2001) or by protein kinase C
(PKC) (Ishaq et al., 2003) has been shown to enhance
the repression function of SMRT. Likewise, Pak1
phosphorylates corepressor CtBP and modulates its
corepressor functions (Barnes et al., 2003). The results
from the present study suggest that Pak1 interacts with
and phosphorylates SHARP in its C-terminal repression
domain, which has been previously shown to interacts
with SMART (Shi et al., 2001). Cotransfection of Pak1
also promoted the repression activity of SHARP, while
downregulation of Pak1 function or mutation of Pak1
phosphorylation sites in SHARP interfered with
SHARP repression. Since SHARP is a SMRT/
HDAC1-associated repressor protein (Shi et al., 2001),
Pak1 phosphorylation of SHARP may promote its
repressor functions in a way similar to PKC phosphorylation of SMART by enhancing its interactions with
SMART. Alternatively, it is also possible that SHARP–
Pak1 interaction may allow Pak1 recruitment to the
corepressor complex, where Pak1 may phosphorylate

other components of the complex.
SHARP was initially identified as a SMART/HDACassociated protein and was implicated in nuclear
receptor signaling as corepressor (Shi et al., 2001).


Role of Pak1 phosphorylation in Notch signaling
RK Vadlamudi et al

4595
Relative pGa981-6-Luc
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SHARP
Pak1
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d

15000000
10000000
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pGa981-6 luc
Notch E
SHARP (WT)
SHARP (DMT)

Con RNAi
Pak1 RNAi

RTPCR

Relative pGA981-6-Luc activity

TATA
EBNA2
responsive
elements

c
Relative Hes-1 Luc
activity

b

pGa981-6-Luc

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Notch
Activation

HES1
GAPDH

RBP/ CBF-1

Pak1

Repression

Vinculin
Pak1

SHARP

Figure 4 Pak1 interferes with Notch-mediated activation of the RBP-Jk target gene. (a) Schematic representation of the reporter gene
assay used. pGa981/6 luc reporter gene contains four RBP-Jk binding sites. A dominant active form of Notch that lacks extracellular
domain was used to activate RBP-Jk target genes by its constitutive interaction with endogenous RBP-Jk. HEK 293 cells were

cotransfected with a dominant active form of Notch (Notch del E, 100 ng) and pGa981/6 luc (2 mg), along with SHARP or SHARP
(200 ng) þ Pak1 siRNA (200 ng) or SHARP (200 ng) þ Pak1-autoinhibitory domain aa 83–149 (200 ng) expression vectors. Luciferase
reporter activity was measured after 48 h. (b) HEK 293 cells were transfected with an activated form of Notch and pGa981/6 luc
together with either wild-type SHARP or mutant SHARP that lacks Pak1 phosphorylation sites. Luciferase activity was measured
after 48 h. (c) NIH3T3 cells were cotransfected with Hes-1 luciferase reporter (250 ng), a dominant active form of Notch (Notch del E,
1 mg) and either SHARP alone or with Pak1 (500 ng) or Pak1-autoinhibitory domain aa 83–149 (500 ng) expression plasmids.
Luciferase activity was measured following 48 h after transfection. (d) Pak1 was knock down in NIH3T3 using Pak1-specific RNAi.
Following 48 h after siRNA transfection, total RNA was extracted and the expression levels of HES-1 was monitored by RT–PCR
analysis using HES-1-specific primers. GAPDH was used as a control. Pak1 expression was confirmed by Western blotting. Vinculin
was used as control. (e) A working model showing Pak1 regulation of Notch signaling

Subsequent studies showed that SHARP is an essential
component of Notch signaling and plays a role in
rescuing from Notch-dependent inhibition of primary
neurogenesis (Oswald et al., 2002). In this context, Pak1
activation promotes neuronal dendrite initiation (Hayashi et al., 2002). Our finding that Pak1 phosphorylates
SHARP and enhances its repressor functions suggests
that Pak1-mediated phosphorylation of SHARP may
constitute an important mechanism by which Pak1 may
promote dendrite formation. Our findings also raise a
possibility that deactivation of the Pak1 pathway may
be necessary for Notch-mediated productive neuronal
differentiation. It is therefore possible that Notch
activation somehow downregulates Pak1 activity as a
feedback mechanism. CDK5/p35 kinase is widely
expressed in neuronal cells and is shown to phosphorylate Pak1 and downregulate Pak1 activity in neuronal
cells (Nikolic et al., 1998). Notch-mediated activation of
CDK5/p35 kinase either directly or indirectly via

activation of Abl kinase (Giniger, 1998) may constitute

one possible mechanism by which Notch relieves Pak1SHARP-mediated repression.
In summary, we discovered and report here that
SHARP is a Pak1-interacting protein and is a physiologic substrate of Pak1. These findings suggest that both
Pak1 and SHARP may be critical molecules for
repression of Notch target genes such as HES-1, and
that Pak1 phosphorylation of SHARP might be
essential for the productive repression function of
SHARP.
Acknowledgements
We thank Dr D Wu for providing pSuper-EGFP-Pak1siRNA, Dr Ronald Evans for SHARP expression plasmid,
Dr Ronald M Schmid for RBP-Jk-VP16, pGa981/6 luc, Notch
1 del E and Dr Ryoichiro Kageyama for Hes-1 promoter-luc
reporter. This study was supported by NIH Grants 90970 and
80066 (RK).

References
Barnes CJ, Vadlamudi RK, Mishra SK, Jacobson RH, Li F
and Kumar R. (2003). Nat. Struct. Biol., 10, 622–628.

Beatus P and Lendahl U. (1998). J. Neurosci. Res., 54,
125–136.
Oncogene


Role of Pak1 phosphorylation in Notch signaling
RK Vadlamudi et al

4596
Bokoch GM. (2003). Annu. Rev. Biochem., 72, 743–781.
Daniels RH, Hall PS and Bokoch GM. (1998). EMBO J., 17,

754–764.
Galasinski SC, Resing KA, Goodrich JA and Ahn NG. (2002).
J. Biol. Chem., 277, 19618–19626.
Giniger E. (1998). Neuron, 20, 667–681.
Hayashi K, Ohshima T and Mikoshiba K. (2002). Mol. Cell.
Neurosci., 20, 579–594.
Hsieh JJ, Zhou S, Chen L, Young DB and Hayward SD.
(1999). Proc. Natl. Acad. Sci. USA, 96, 23–28.
Ishaq M, DeGray G and Natarajan V. (2003). J. Biol. Chem.,
278, 39296–39302.
Iso T, Kedes L and Hamamori Y. (2003). J. Cell. Physiol., 194,
237–255.
Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z,
Downes M, Kintner CR, Evans RM and Kadesch T.
(1998). Genes Dev., 12, 2269–2277.
Li F, Adam L, Vadlamudi RK, Zhou H, Sen S, Chernoff J,
Mandal M and Kumar R. (2002). EMBO Rep., 3, 767–773.
Li Z, Hannigan M, Mo Z, Liu B, Lu W, Wu Y, Smrcka AV,
Wu G, Li L, Liu M, Huang CK and Wu D. (2003). Cell, 114,
215–227.

Oncogene

Manser E, Leung T, Salihuddin H, Zhao ZS and Lim L.
(1994). Nature, 367, 40–46.
Miele L and Osborne B. (1999). J. Cell. Physiol., 181, 393–409.
Nikolic M, Chou MM, Lu W, Mayer BJ and Tsai LH. (1998).
Nature, 395, 194–198.
Ohtsuka T, Ishibashi M, Gradwohl G, Nakanishi S, Guillemot
F and Kageyama F. (1999). The EMBO J, 18, 2196–2207.

Oswald F, Kostezka U, Astrahantseff K, Bourteele S,
Dillinger K, Zechner U, Ludwig L, Wilda M, Hameister
H, Knochel W, Liptay S and Schmid RM. (2002). EMBO J.,
21, 5417–5426.
Schweisguth F. (2004). Curr. Biol., 14, R129–R138.
Shi Y, Downes M, Xie W, Kao HY, Ordentlich P, Tsai CC,
Hon M and Evans RM. (2001). Genes Dev., 15, 1140–1151.
Thiel DA, Reeder MK, Pfaff A, Coleman TR, Sells MA and
Chernoff J. (2002). Curr. Biol., 12, 1227–1232.
Vadlamudi RK and Kumar R. (2003). Cancer Metast. Rev.,
22, 385–393.
Zhou S and Hayward SD. (2001). Mol. Cell. Biol., 21,
6222–6232.
Zhou Y, Gross W, Hong SH and Privalsky ML. (2001). Mol.
Cell. Biochem., 220, 1–13.