Abstract
Animal Cells and Systems 13: 9-15, 2009 Identification of WDR7 as a Novel Downstream T arget of the EphA8-Odin Signaling Complex Eunjeong Park and Soochul Park* Department of Biological Science, Sookmyung W omen’ s University , Seoul 140-742, Korea Abstract: Eph rece ptors and thei r eph rin l ig ands ha v e b een and survival (Kullander and Klein, 2002). Their unique implicated in a variety of cellular processes such as cellular bidirectional signaling mechanism has emerged as a key morph ogenesi s an d motil ity . O u r prev io us studi es demonstrated determinant of various developmental processes, including that Odin, one of the Anks family proteins, functions as a cardiovascular and skeletal development, axon guidance, scaffolding protein of the EphA8 signaling pathway leading synaptogenesis, and tissue patterning (Palmer and Klein, to modulation of cell migration or axonal outgrowth. Here we 2003). show that WDR7 is associated with Odin and that it is possibly implicated in the EphA8 signaling pathway. WD40 A well-known ef fect of Eph signaling is retraction of the repeats present in the COOH-terminal region of WDR7 cell periphery following contact with ephrin-expressing appear to be crucial for its association with Odin, whereas cells (Pasquale, 2005). This repul sive event may be essential the binding motif of Odin is located in between ankyrin for axo n guidance and sorting of Eph-ex p re ssing cells from re peat s and P T B domain . C o -immunopr ecipi t ation e x perimen t s ephrin-expressing cells during developmental process revealed that association of WDR7 with Odin is enhanced (Pasquale, 2008). Two different mechanisms can explain by ephrin ligand treatment, possibly through forming large how Eph-ephrin-mediated adhesive response is turned into protein complexes including both EphA8 and ephrin-A5. Consistently, immunofluorescence staining experiments repulsion. One mechanism is to eliminate the Eph-ephrin suggested that WDR7 constitute a component of the large complexes from the cell surface due to endocytosis of protein complexes containing Odin, EphA8 and ephrin-A5. plasma membrane portions derived from both cells (Egea Taken together, our results suggest the WDR7-Odin complexes and Klein , 2007). The other mech anism is metallop rotease- might be involved in the signaling pathway downstream of mediated cleavage of ephrins (Egea and Klein, 2007; the EphA8 receptor. Himanen et al., 2007). In addition to how Eph receptors Key words: Odin, Anks family protein, EphA8, WDR7 control repulsion versus attraction, the interplay between Eph signaling and various signaling molecules has been predicted to be a key factor in the control of its ultimate INTRODUCTIONeffects on cell behavior. AβPP intracellular domain-associated protein 1b (AIDA- The Eph family, the largest subfamily of receptor tyrosine 1b) and Odin (a deity in the Nordic mythology) belong to kinases (RTKs), is comprised of at least sixteen different the ankyrin repeat and sterile alpha motif (SAM) domain receptors. They bind to cell surface-attached ephrin ligands containing (Anks) protein family. It has been known that on the contacting cells, which have been identified up to ten AIDA-1b and Odin participate in modulating A βPP different members to date. Eph-ephrin complexes can processing and inhibiting platelet-derived growth factor- transduce bidirectional signals (in trans) which influence mediated cell proliferation, respectively (Pandey et al., both the Eph receptor-expressing cells (forward signaling) 2002; Ghersi et al., 2004). More recently , the Anks family and the ephrin-expressing cells (reverse signaling). Unlikeproteins have been identified as a scaffolding protein which other RTKs, Eph receptors do not regulate cell proliferation modulates the EphA8 signaling pathway related to cell motility and axonal retraction (Shin et al., 2007). In the present stud y , we identified WD Repeat 7 (WDR7) * T o whom correspondence should be addressed. as an adaptor protein that interacts with Odin through two T el: +82-2-710-9330; Fax: +82-2-715-9331 WD40 repeats in its C-terminal portion. WD40 repeats are E-mail: scpark@sookmyung.ac.kr ANIMAL CELLS AND SYSTEMS Vo l. 13 No. 1 9 Eunjeong Park and S oochul P ark conserved domains containing approximately 40-60 amino with Odin in binding buffer (20 mM Tris-HCl (pH 7.5), acids. They are initiated by a glycine-histidine (GH) dipeptide 5 mM EDT A, 100mM NaCl, 0.1% T riton X-100) for 2 h at from the N terminus and end with a tryptophan-aspartic 4 C. After removal of the supernatant, the beads were acid (WD) dipeptide at the C terminus. Between the GH washed three times with the same buf fer , and bound proteins and WD dipeptides is the conserved core sequence (Smith were separated by sodium dodecyl sulfate-polyacrylamide et al., 1999; Li and Roberts, 2001). In general, WD40 gel electrophoresis (SDS-PAGE). Precipitated Odin was repeat proteins have been implicated in a wide spectrum ofdetected by immunoblotting with anti-Odin antibody. cellular processes, including RNA processing, transcriptional Co-immunoprecipitation and Western blotting regulation (Williams et al., 1991; Hoey et al., 1993), mitotic spindle formation (de Hostos et al., 1991; Vaisman et al., Co-immunoprecipitation and Western blotting were 1995), regulation of vesicle formation and vesicular performed as described previously (Gu et al., 2001). 293T trafficking (Pryer et al., 1993), and control of cell division cells were cotransfected with hemagglutinin (HA)-tagged (Feldman et al., 1997). WDR7 does not have other knownWDR7 and Odin. After 24h, transfected cells were harvested protein-protein interacting motifs or catalytic domains and cell lysates were prepared with protease inhibitors in except for nine WD40 repeats. Although it has been PLC buffer (50 mM HEPES (pH 7.5), 150 mM NaCl, implicated in Rab3A-mediated exocytosis of neurotransmitter 1.5 mM MgCl , 1 mM EG T A, 10% glycerol, 100 mM NaF , through its interaction with Rab3 GDP/GTP exchange 1mM Na VO , and 1% Triton X-100). To purify target 3 4 protein (Rab3 GEP), its function is largely unknown proteins, 1 µ g of affinity-purified polyclonal antibody was (Sanders et al., 2000; Nagano et al., 2002; Kawabe et al.,incubated with precleared cell lysate for 1h at 4C and then 2003). Our current findings raised the possibility for the precipitated with protein A-Sepharose (GE Healthcare) for first time that WDR7-Odin complexes may play a critical 1 h at 4 C. The resulting proteins were resolved by SDS- role in the regulation of EphA8 receptor endocytosis. PAGE and subjected to Western blot analysis by the indicated antibodies. MA TERIALS AND METHODS Immunofluorescence staining Y east two-hybrid screen Immunofluorescence staining was performed as described The mouse Odin- ∆PTB (with a deletion of amino acids 865 previously (Shin et al., 2007). 293 cells were stably to 1082 of mouse Odin) cloned into the pBHA vector transfected with WDR7 and EphA8. The indicated cells (pEP11) was used as bait to screen a human fetal brain were transfected with EYFP-tagged Odin. The cells were cDNA library consisting of 3.0 ×10 independent clones stimulated with preclustered ephrinA5-Fc ligands or Fc (Clontech). Briefly, yeast strain L40 [MATa his3200 trp1- control for 15 min and fixed with 4% paraformaldehyde- 901 lue2-3,1 12 ade2 (LYS2::lexAop) -HIS3 (URA3::lexAop) - 2% sucrose in pho sphate-buf fered salin e for 20 min at room 4 8 lacZ GAL4] was transformed with pEP11 and the human temperature, and rinsed three times for 5 min with TBST fetal brain cDNA library as described previously (Shin et (50 mM T ris-HCl (pH 7.4), 150 mM NaCl, 0.1% T riton X- al., 2007). The resulting transformants were screened for 100). Cells were blocked with TBST containing 5% horse histidine prototrophy by using 1 mM 3-aminotriazole (3- serum for 30 min at room temperature and then incubated AT) on selective medium lacking His, Trp, and Leu. with primary antibodies overnight at 4 C. After washing, Histidine-positive (His ) clones were then assayed for blue cells were incubated with immunofluorescence-conjugated coloring by colony lift with 5-bromo-4-chloro-3-indolyl- β- secondary antibodies for 1 h at room temperature. Photos + + D-galactopyranoside (X-Gal). Among several His LacZ were taken with a confocal microscope (model FV300; clones, five identical clones encompassing the COOH-Olympus). terminal portion of WDR7 gene (GenBank accession no. NM-015285) were identified. Antibodies A polyclonal rabbit antibody specific for the JM domain of In vitro binding assay EphA8 was described previously (Choi et al., 1999). Anti- Binding assays were performed as described previously WDR7 antibodies were a gift from Dr. Yoshimi Takai. (Gu et al., 2001). Purified glutathione S-transferase (GST)- Anti-Odin antibodies were purchased from Calbiochem, tagg ed th e COOH-terminal po rtion of WDR7 (G ST -W7-C) anti-HA antibodies from Zymed, and tetramethyl rhodamine protein (amino acids 1149 to 1490 of human WDR7) was isocyanate-conjugated goat anti-rabbit IgG and fluorescein immobilized onto glutathione-Sepharose 4B beads (GE isothiocyanate (FITC)-conjugated goat anti-rabbit IgG Healthcare). The GST-W7-C immobilized beads were an tib od ies from Ch em ico n. H o r s e r a d i sh pe r o xi da se-con ju ga ted incubated with lysate prepared from 293T cells transfectedanti-rabbit IgG antibodies were purchased from Zymed. 10 ANIMAL CELLS AND SYSTEMS Vol. 13 No. 1 WDR7 Interacts w ith O din RESUL TS AND DISCUSSION WDR7 is able to interact with Odin through two WD40 repeats present in its C-terminal portion. Fetal brain cDNA library screening identifies WDR7 as an Odin-interacting protein Treatment with ephrin ligand enhances the specific Our previous studies indicated that Odin is a scaffolding association between Odin and WDR7 proteins protein to regulate the EphA8-mediated signaling pathway Next, we examined whether a full-length WDR7 protein leading to cell migration and axonal retraction. Odin protein forms a stable complex with Odin protein in cultured cells. c o n t a i n s v a r i o u s c o n s e r v e d d o ma i n s i n c l u d i n g a n k yr i n repeat, Expression vector encoding the full-length Odin protein sterial alpha motif (SAM) and phosphotyrosine binding was co-transfected into 293T cells together with a vector (PTB) domain. To further elucidate how Odin protein encoding HA-tagged WDR7 protein. Cell lysates were regulate the EphA8-mediated signaling pathway, we immunoprecipitated by anti-Odin antibody, followed by performed a yeast two-hybrid screen in which the Odin immunoblotting with anti-HA antibody. As shown in Fig. protein lacking its PTB domain (Odin- ∆PTB) was used as a 2A, the WDR7 protein was readily detected in anti-Odin bait to screen a human fetal brain cDNA library (Fig. 1A). immunoprecipitates (lane 4). The robust co-immuno- We have identified five different clones as putative precipitation of WDR7 with Odin was dependent on the candidates, and one of them corresponds to the COOH- expression of Odin (lanes 2 and 4), although nonspecific terminal portion of WDR7 protein. WDR7 is known to precipitation was also detectable in an immune complex have nine WD40 repeats and the interacting clone, W7-C, which a rabbit IgG antibody replaced the anti-Odin contains two WD40 repeats present in its COOH-terminus antibody (lane 5). Consistent with these data, our co- (Fig. 1A). immunoprecipitation study using anti-WDR7 antibody As shown in Fig. 1B, we confirmed the association of demonstrated that Odin was specifically co-precipitated int er a cti ng c lon e W 7 - C w i t h the O din - ∆ P T B b y t ran sfo rm i n gwith WDR7 from cell lysates (Fig. 2B, lane 4). them back into yeast. In contrast, yeast transformants To further investigate whether an increased association expressing either ankyrin repeats or SAM domains together between Odin and WDR7 requires the ephrin ligand − − − with W7-C did not grow on His Trp Leu selective plates stimulation, 293T cells transiently transfected with WDR7, (Fig. 1B, left panel) and failed to show X-Gal staining on Odin and EphA8 expression constructs were treated with - - Trp Leu selective plates (Fig. 1B, right panel), suggesting preclustered ephrinA5-Fc ligands for 15 min, and cell that certain motif(s) existing in b etween ankyri n repeats and lysates were subjected to an immunoprecipitation assay SAM domains is likely to be critical for interaction with using anti-Odin antibody (Fig. 2C). Consistent with our WDR7. previous report, EphA8 was co-immunoprecipitated with In order to demonstrate a direct interaction between the Odin in response to ephrinA5-Fc treatment (third panel, Odin protein and W7-C, the W7-C interacting clone waslane 2). Additionally, it was evident that the level of WDR7 expressed as a bacterial GST fusion protein and mixed with protein co-immunoprecipitated with Odin was strongly the lysates of 293T cells expressing Odin protein for the elevated in response to preclustered ephrinA5-Fc, but not GST pull-d o wn exp eriment. T ransfectio n of Odin construct with Fc (first panel). T aken together , these findings suggest into 293T cells elevates the expression level of Odin at least that association of WDR7 with Odin is enhanced by ephrin by 5-fold as compared with that of the endogenously ligand treatment, suggesting a functional significance of expressed Odin (data not shown). As expected, the GST WDR7-Odin complexes in EphA8-ephrin-A5 signaling . fusion protein of W7-C, but not GST , was specifically co- precipitated with Odin protein not only from control cells WDR7 is co-localized with Odin and EphA8/ephrin- but also from cells over-expressing Odin (Fig. 1C). These A5 complex results indicate that the C-terminal region of WDR7 is It has been previously shown that Odin is a cytoplasmic sufficient to associate with the full-length Odin protein in protein negatively acting downstream of the EGF signaling vitr o. pathway (Pandey et al., 2002). WDR7 is also a cytoplasmic Next, we investigated wh ether the WD40 repeats in W7- protein involved in vesicle trafficking, and our immuno- C mediate its interaction with Odin. For this experiment, fluorescent staining using WDR7 antibody revealed that we constructed Xpress-tagged W7-C protein (W7-C ∆WD) W D R7 is uni for ml y dist ribut ed in the cy toplas m of 293 cel ls lacking two WD40 repeats (Fig. 1A), and this deletion (Fig. 3, fifth panels from left). Since both Odin and WDR7 mutant was co-expressed with the full-length Odin in 293T antibodies were derived from rabbits, enhanced yellow cells for co-immunoprecipitation experiments. As expected, fluorescent protein (EYFP)-tagged Odin construct was the full-length Odin interacted strongly with W7-C (Fig. generated for co-localization study. Although Odin is 1D, lane 4 from left) but failed to bind to W7-C ∆ WD (lane predicted to be mainly present in the cytoplasm, EYFP- 8 from left). Taken together, these results suggest that tagged Odin was observed in both cytoplasm and nucleus, ANIMAL CELLS AND SYSTEMS Vo l. 13 No. 1 11 Eunjeong Park and S oochul P ark Fig. 1. Odin interact s with the WDR7 protein. (A) Domain structures of Odin, Odin- ∆ P TB (with a deletion of amino acids 865 to 1082 of mouse Odin), WDR7, W7-C (amino acids 1149 to 1490 of human WDR7), and W7-C ∆ WD (with a deletion of amino acids 1351 to 1432 of W7-C). SAM, SAM domain; Ank, ankyrin repeat domain; PTB, PTB domain; WD, WD40 repeats domain. (B) Growth and X-Gal staining analysis indicated that the interacting clone, W7-C binds to Odin- ∆ PTB. W7-C was co-expressed in the yeast two-hybrid assay with the LexA DN A binding domai n al one or wi th LexA fus i ons t o t he O d in- ∆ P T B, a n k yr i n r epeat dom ain of O d in ( O di n - Ank ) and SAM do main of Odi n ( O din- SAM). − − − − − Y eas t trans for mant s we re c u lt ured on Hi s Tr pLeu s e lec t iv e plates i n the pres enc e of 1 mM 3-A T ( l ef t p anel) and on T r p Leu s e lec t iv e plates in the absence of 3-A T prior to X-Gal staining using a filter-lifting method (right panel). Y east cells transformed with the ty rosine kinase domain − − − (TKD) of EphA8 as bait served as a negative control. Y east transformants showing negative growth on His Trp Leu selective plates in the − − presence of 1 mM 3-AT failed to show X-Gal staining on Trp Leu selective plates. (C) Demonstration of the C-terminal region of WDR7 interaction with the full-length Odin protein. Purified proteins (GST or GST-W7-C) were mixed with whole-cell lysates from 293T cells transfected with the control vector (lanes 1 and 3) or an Odin expression construct (lanes 2 and 4). Bound proteins were pulled down using glutathione beads . T he wa s hed beads we re s e p a rated by 10 % SD S-P A G E an d W e st ern blotted ( W B) us ing anti- Odin antibody as a probe (t op p anel) . T h e same blot was stripped and reprobed with anti-GST antibody (middle and bottom panel). (D) Co-immunoprecipitation of W7-C and Odin in 293 T cells (left panels). Cells were transfected with Xpress-tagged W7-C and Odin as indicated in each lane. Then total cell lysates were immunoprecipitated with anti-Xpress antibody and subjected to Western blotting with anti-Odin (first panel). The same blot was stripped and r eprobed wi t h anti- Xp res s antibody (s ec ond p anel). A s a mp l e (3%) of eac h t o t a l c e ll l ys a t e wa s analyz ed di rec t ly by W e st ern blo tt ing us ing anti- Odin antibody and anti-Xpress antibody (third and fourth panel). Co-immunoprecipitation of W7-C ∆ WD and Odin in 293T cells (right panels). Experiments were performed essentially as described for left panels, except that W7-C ∆ WD was used. Experiments shown in panel D were performed at the same time. PD, Pulldown; WB, Western blot; WCL, whole-cell lysate. 12 ANIMAL CELLS AND SYSTEMS Vol. 13 No. 1 A Fig. 2. EphrinA5 stimulation enhances the specific complex formation of Odin with WDR7 proteins. (A) Co-immunoprecipitation of WDR7 and Odin in 293T cells. Cells were transfected with HA- tagged WDR7 and Odin as indicated in each lane, and then total cell lysates were immunoprecipitated with anti-Odin antibody, followed by immunoblotting with anti-HA antibody (first panel). The same blot was stripped and reprobed with anti-Odin antibody (second panel). A sample of each total cell lysate was analyzed dir ectly by W estern blotting using anti-HA antibody and anti-Odin antibody (third and fourth panel). (B) Reciprocal co-immunoprecipitation of WDR7 and Odin in 293T cells. Experiments were perfo rmed essentially as described for panel A, except tha t reciprocal antibodies were used, as indicated in each panel. (C) 293T cells were transiently transfected with WDR7, Odin and EphA8 expression constructs. After 24 h, cells were stimulated with preclustered ephrinA5-Fc ligands for 15 min. T otal cell lysates were immunoprecipitated with anti-Odin antibody or control IgG and then immunoblotted with anti-HA antibody (first panel). The same blot was stripped and reprobed with anti-Odin antibody and anti-EphA8 antibody (second and third panel). A sample of each total cell lysate was analyzed directly by Western blotting using anti-HA antibody , anti-Odin antibody and anti-EphA8 antibody (fourth, fifth and sixth panel). IP , Immunoprecipitation; WB , Western blot; WCL, whole-cell lysate. n Eunjeong Park and S oochul P ark Fig. 3. WDR7 is co-localized with Odin and EphA8/ephrin-A5 complex in the cytoplasmic region. 293 cells were stably transfected with WDR7 and EphA8 receptor. The cells were stimulated with preclustered ephrinA5-Fc ligands or Fc control for 15 min and stained with anti-WDR7 antibody (first panels, second panels and third panels from left). The indicated cells were transfected with EYFP-tagged Odin. The cells were stimulated and stained with as described for previously (fourth panels, fifth panels and sixth panels from left). s ugge st ing th at O din m a y b e t r ans l oca te d f r o m t he cy t opla s m ACKNOWLEDGMENTS to the nucleus in the presence of certain biochemical stimulation. Nevertheless, the cytoplasmic EYFP-tagged We thank Dr. Y oshimi Takai for providing the WDR7 construct and its antibody. This work was supported by Sookmyung Od i n a p p e a rs to b e c o -lo c a l i z e d we ll wi th WDR7 , irre sp ec ti v e Women’s University in 2007. of ephrin-A5 treatment (Fig. 3, sixth panels from left). Since both Odin and WDR7 are uniformly distributed possibly as the sa me protein complex in the cytoplasm, it seems dif ficult REFERENCES to demonstrate a clear-cut and enhanced co-localization of Choi SA and Park SC (1999) Phosphorylation at Tyr-838 in the these two proteins in response to ephrin-A5 stimulation. 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Journal
Animal Cells and Systems
– Taylor & Francis
Published: Jan 1, 2009
Keywords: Odin; Anks family protein; EphA8; WDR7
