Article |
Address correspondence to Kenneth S. Kosik, Dept. of Neurology, Brigham and Women's Hospital and Harvard Medical School, Harvard Institute of Medicine, 77 Ave. Louis Pasteur, Boston, MA 02115. Tel.: (617) 525-5230. Fax: (617) 525-5252. E-mail: kosik{at}cnd.bwh.harvard.edu
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Abstract |
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Key Words: -catenin; cortactin; Rho; dendritic branching; tyrosine phosphorylation
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Introduction |
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Small GTPases, which play a major role in actin organization, have been shown to be involved in the regulation of neuronal cell morphology including neuritogenesis. The role of RhoA in process formation was first demonstrated in studies using the Rho-specific ADP-ribosyltransferase C3 toxin (Clostridium botulinum C3 Rho-ADPribosylating exoenzyme), which could induce neurites in PC12 cells even without NGF treatment (Nishiki et al., 1990). Many additional studies have shown that RhoA is involved in the regulation of neurite outgrowth (Tigyi and Miledi, 1992; Jalink et al., 1994; Kozma et al., 1997; Zipkin et al., 1997; Lehmann et al., 1999; Sebok et al., 1999; Nakayama et al., 2000). Studies of neurite branching often focus on axons; however, dendritic branching is morphologically distinct from axonal branching with regard to tapering and branching patterns (Desmond and Levy, 1984). A role for RhoA in dendritic branching has been suggested. RhoA activation leads to a reduction in dendritic branching (Nakayama et al., 2000), and RhoA inhibition enhances branching (Neumann et al., 2002). Mediators of RhoA, such as Rho kinase, support these opposite effects on branching (Katoh et al., 1998). Likewise, Cip1/WAF1 inhibits Rho kinase and promotes neurite outgrowth and branching in hippocampal neurons (Tanaka et al., 2002). A distinct branch of the Rho GTPase family, the Rnd proteins, control rearrangements of the actin cytoskeleton and changes in adhesion (Nobes et al., 1998). Rapostlin, an effector for Rnd2, can induce neurite branching when expressed in NGF-treated PC12 cells (Fujita et al., 2002). A genetic screen in Drosophila identified several genes that control aspects of dendrite development including dendritic outgrowth, branching, and routing (Gao et al., 1999).
Because neuronal process elaboration must involve adhesive changes concomitant with extension into the neurophil, it is not surprising that adhesion molecules will be represented in this molecular toolbox. The p120ctn family, which consists of a family of proteins with 10 Armadillo (Arm)* repeats characteristically spaced, are increasingly recognized for their dual roles in regulating adhesion and process elaboration. Coordinating these two functions is very likely a key role for the cadherin juxtamembrane sequence where all of these family members bind. -Catenin is a neuronal specific member (Ho et al., 2000) of this protein family, which also includes p120ctn, ARVCF, and p0071. Like p120ctn,
-catenin can radically change cell morphology when overexpressed in fibroblasts (Reynolds et al., 1996; Kim et al., 2002).
The implementation of process elaboration requires reorganization of the actin cytoskeleton, and indeed linkages between the adherens junction and the actin cytoskeleton are well recognized. ß-Catenin binds both to the COOH terminus of classical cadherins and to -catenin, which binds directly or indirectly to actin (Yamada and Geiger, 1997). A second linkage through the p120ctn family of proteins can be surmised based on functional studies, but the actual components or pathway is unknown. Potentially, most informative is the extension of data derived for p120ctn to
-catenin. Like
-catenin, p120ctn induces a "branching phenotype" (Reynolds et al., 1996; Kim et al., 2002). An interaction between p120ctn and Rho1 and an accumulation of Rho1 in adherens junctions occurs in Drosophila (Magie et al., 2002). p120ctn inhibits Rho (Anastasiadis et al., 2000; Noren et al., 2000), and cadherin binding to p120ctn functions as a regulator of adhesion through Rho GTPases (Anastasiadis and Reynolds, 2001).
Cortactin is a linker protein to the actin cytoskeleton, which is well suited to couple tyrosine kinase signaling between membrane proteins and the cytoskeleton (Weed and Parsons, 2001). A centrally positioned series of repeats in cortactin bind and cross-link actin filaments in a tyrosine phosphorylationdependent manner (Wu and Parsons, 1993; Huang et al., 1997). Through binding to the Arp2/3 complex, cortactin provides a site for actin filament nucleation (Weed et al., 2000; Uruno et al., 2001). Additionally, Rho GTPases can determine cortactin association with the actin system and contractile regulation in endothelial cells (Garcia et al., 1999). Here, we show that -catenin binds cortactin in a tyrosine phosphorylationdependent manner that depends on Src family kinases. Inhibition of these kinases enables
-catenincortactin complex formation and the growth of primary neurites. On the other hand, inhibition of the RhoA pathway together with expression of
-catenin further enhances the extension of secondary neurites.
-Catenin appears positioned to regulate neurite growth through two separate pathways that balance primary process extension with branch formation.
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Results |
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-Catenin is a Src family substrate
To determine the family of tyrosine kinases responsible for phosphorylating -catenin,
-PC12 cells were treated with several tyrosine kinase inhibitors. We found that a treatment with PP2 (25 µM), a Fyn/Lck/Hck tyrosine kinase inhibitor (Fig. 7 A), was able to abolish endogenous
-catenin phosphorylation in
-PC12 cells. Nonreceptor tyrosine kinases are good candidates because p120ctn is a known Src substrate (Kanner et al., 1991; Reynolds et al., 1992) and
-catenin is an in vitro substrate for Abl (Lu et al., 2002). In
-PC12 cells, the basal level of tyrosine phosphorylation on
-catenin can be completely inhibited by PP2 (Fig. 7 A). In primary cultured neurons, endogenous
-catenin is only minimally tyrosine phosphorylated, but after H2O2 treatment, which can induce tyrosine phosphorylation of
-catenin (Fig. 6 B), 25 µM PP2 completely inhibited
-catenin tyrosine phosphorylation as detected by a phosphotyrosine antibody (Fig. 7 A). When Fyn was transfected into
-PC12 cells,
-catenin phosphorylation increased (Fig. 7 B), but endogenous phosphorylation was not abolished when a dominant-negative form of Fyn (Fyn K299M) was transfected, raising the possibility that other members of the Src family phosphorylate
-catenin. Several
-catenin deletion constructs were tested for H2O2-induced tyrosine phosphorylation, and the specific constructs on which tyrosine phosphorylation was induced by H2O2 matched the constructs on which Fyn transfection induced tyrosine phosphorylation (unpublished data). In addition to serving as a substrate for a Src family tyrosine kinase, a FynSH3GST construct and a LckSH3GST construct pulled down
-catenin in transfected COS1 cells and in neurons (Fig. 7 C). Neither FynSH3 nor LckSH3 pulled down FL
P6, a
-catenin construct which lacked the polyproline track (Fig. 7 C). Together, this data suggest that a Src family nonreceptor tyrosine kinase binds to
-catenin through its polyproline tract and phosphorylates
-catenin.
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We next asked whether the activation of tyrosine phosphorylation in primary neurons could induce the dissociation of the -catenincortactin complex. When primary neurons were treated with H2O2 for 5 min or with H2O2 (200 µM) plus orthovanadate (1 mM), the interaction between cortactin and
-catenin was abolished (Fig. 6 B), whereas the
-cateninN-cadherin interaction was preserved. This observation suggested that the
-catenincortactin interaction depends on the tyrosine phosphorylation state of the cell and possibly on the tyrosine phosphorylation state of
-catenin and/or cortactin. Interestingly, treatment of the hippocampal neurons with brain-derived neurotrophic factor (BDNF) (50 ng/ml) for 60 min also induced
-catenin phosphotyrosine immunoreactivity and dissociation of the
-catenincortactin complex (Fig. 6 C). Thus, two different cell types, primary neurons and
-PC12 cells, with different basal levels of
-catenin tyrosine phosphorylation have consistent
-catenincortactin complex association or dissociation in response to increasing or decreasing their state of tyrosine phosphorylation.
Primary process elongation versus branching
The inhibition of -catenin tyrosine phosphorylation in NGF-treated
-PC12 cells exposed to PP2 (25 µM for 1 h) enhanced the morphological changes induced by
-catenin (Fig. 8). The total length of the processes increased from 15.1 ± 1.2 to 24.9 ± 2.4 µm (P < 0.0001), and the number of primary processes increased from 3 ± 0.26 to 5.1 ± 0.37 (P < 0.0001), but there was no change in the number of branches or secondary processes (Fig. 8 B). Wild-type PC12 cells, which have negligible if any
-catenin, were unaffected by PP2 (unpublished data).
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Discussion |
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The interaction between -catenin and cortactin is mediated by tyrosine phosphorylation as suggested by dissociation of the complex with increased Src family tyrosine kinase activity. Both
-catenin and cortactin can be extensively tyrosine phosphorylated. Indeed, many proteins that are tyrosine phosphorylated by Src kinase family members are involved in actin organization including ezrin-radixin-moesin proteins, p120ctn, ß-catenin, tensin, focal adhesion kinase, Crk-associated substrate, and actin filamentassociated protein (Kanner et al., 1990). Moreover, cortactin directly and specifically binds endothelial cell myosin light chain kinase, and the interaction can be regulated by Src-mediated tyrosine phosphorylation of either protein (Dudek et al., 2002). Tyrosine phosphorylation of the potassium channel Kv1.2 also regulates its binding to cortactin (Hattan et al., 2002).
Positioned at a membrane proximate site, -catenin can influence dynamic cortical actin assembly through its recruitment of cortactin (Weed et al., 2000) in a phosphorylation-dependent manner. One potential role of the
-catenincortactin interaction is to modulate the effects of cortactin on Arp2/3 actin polymerization. The Arp2/3 complex, comprising seven polypeptides, regulates both the formation and structure of actin networks directly (May, 2001). By dramatically increasing the nucleation rate, the Arp2/3 complex generates the large number of new filaments needed for actin network formation and helps create the branched network by cross-linking the slow growing pointed end of one filament to the side of another. However, Arp2/3 complexmediated cross-links are relatively labile, and cortactin may stabilize Arp2/3 complexmediated branches (Weaver et al., 2001). The role of cortactin and Arp2/3 complex in modulating the neuronal cytoskeleton in favor of neurite outgrowth is poorly understood, but
-catenin could serve to localize protrusions to sites of neuronal activity. Both proteins also interact with postsynaptic scaffolding proteins: SHANK in the case of cortactin (Naisbitt et al., 1999) and S-SCAM in the case of
-catenin (Ide et al., 1999). Multiple possibly redundant pathways leading to neurite extension converge around the Src kinasemediated cortactin interactions. These include N-syndecan, a neurite outgrowth receptor that can bind the nonreceptor tyrosine kinase Src and its substrate, cortactin (Kinnunen et al., 1998), and the neural Wiskott-Aldrich syndrome protein (N-Wasp), which plays an essential role in neurite extension in PC12 cells and rat hippocampal primary culture cells (Banzai et al., 2000). N-Wasp and cortactin can bind simultaneously to the Arp2/3 complex and activate actin assembly (Weaver et al., 2002).
Modulation of neurite complexity
A balance between process elongation and branching is critical for the cell to achieve its ultimate shape. These two morphologic phenotypes may operate by distinct but not necessarily autonomous signaling pathways. Extensively branched processes regulated by Rho or primary process extension with minimal secondary branching regulated by Src are both induced in association with -catenin expression (Fig. 10). When Rho is inhibited, processes tend to branch, and when Src family tyrosine kinase activity is reduced, processes elongate without branching (Fig. 10). The ability of
-catenin to enhance the effect of C3 could imply that C3 incompletely inhibits Rho-related proteins and
-catenin allows further inhibition (indeed p120ctn potently inhibits RhoA), or
-catenin affects related pathways similar to the ability of p120ctn to increase the activity of endogenous Cdc42 and Rac1 (Noren et al., 2000). A signaling node where these effects might be coordinated is through p190RhoGAP. The activity of some regulators of Rho such as p190RhoGAP can be modified by Src family phosphorylation (Arthur et al., 2000; Brouns et al., 2001). Stimuli that activate Src might modulate both pathways. An increase in tyrosine kinase as induced by H2O2 would have convergent inhibitory effects on process elaboration by both relieving the inhibition on Rho activity and dissociating the cortactin
-catenin complex. Under more physiologic circumstances, these effects might be regulated by neurotrophins, which can abolish Rho activation when bound to p75 receptor (Dailey and Smith, 1996) and, in the case of BDNF, activate Fyn kinase (Narisawa-Saito et al., 1999) via the TrkB receptor. Thus,
-catenin is well positioned to mediate a balance between process elongation and branching: when Rho is inhibited processes tend to branch and when Src family tyrosine kinase activity is reduced processes elongate without branching (Fig. 10). The relative balance of these activities may mediate process morphology.
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Materials and methods |
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Immunofluorescence
For immunostaining, neurons cultured on coverslips were washed once in PBS and fixed with 4% PFA in PBS for 15 min RT, washed twice in PBS, and then permeabilized for 5 min in PBS containing 0.2% Triton X-100. Cells were washed twice in PBS, blocked in 10% normal goat serum for 30 min RT and exposed to primary antibodies in PBS containing 1% normal goat serum overnight at 4°C. Secondary antibodies were Alexa 594 goat antirabbit and Alexa 488 goat antimouse. Coverslips were mounted in GEL/MOUNT TM (Biomeda). Each fluorescence image was acquired using a confocal laser scanning unit coupled to a Zeiss Axiovert S100 (Carl Zeiss MicroImaging, Inc.).
Antibodies and other chemicals
An affinity-purified antibody (Ab62) raised against a -catenin peptide corresponding to aa 434530 was described previously (Lu et al., 1999), and monoclonal
-catenin antibody was from Transduction Laboratories, Inc. Polyclonal anticortactin antibody was from Santa Cruz Biotechnology, Inc., monoclonal anti-MAP2 was from Chemicon, Inc., monoclonal antitubulin was from Sigma-Aldrich. Monoclonal anti-HA antibody was from Santa Cruz Biotechnology, Inc. Normal mouse IgG was from Santa Cruz Biotechnology, Inc., and Alexa 594 goat antirabbit IgG, Alexa 488 goat antimouse IgG, and Phalloidin 594 were from Molecular Probes, Inc.
PP2 (a Src family tyrosine kinase inhibitor with specificity for Fyn, Lck, and Hck) and BDNF were purchased from Calbiochem and used at the concentrations indicated in Results. NGF was purchased from Roche, Inc.
Plasmids
Cloning of full-length -catenin in pEGFP vector (CLONTECH Laboratories, Inc.) was described previously (Lu et al., 1999). Several
-catenin deletion constructs in pEGFP were generated by restriction digests:
C205 and
C332 using the NruI and StuI sites in
-catenin, respectively.
C99 construct was generated by PCR using the QuikChange® Site-Directed Mutagenesis kit (Stratagene) for introducing two-stop codons right after aa number 1,148. FL
P6 lacking the polyproline track (219224), was generated using the QuikChange® Site-Directed Mutagenesis kit (Stratagene).
The fusion proteins for GSTSH3 domain of mouse Fyn (85139) and Lck (54120) were from Santa Cruz Biotechnology, Inc. GSTmouse full-length cortactin and GSTCTcortactin (aa 287509) were provided by Sheila Thomas (Fred Hutchinson Cancer Research Center, Seattle, WA). Mouse cortactinFlag construct in pCDNA3 was provided by J.T. Parsons (University of Virginia Health Sciences Center, Charlottesville, VA). Human Fyn and dominant-negative Fyn K299M constructs in pCMV5 vector were provided by Marilyn D. Resh (Memorial Sloan Kettering Cancer Center, New York, NY). Plasmids corresponding to RhoV14 and C3 were provided by Jeff Settleman (Massachusetts General Hospital, Charlestown, MA).
Immunoprecipitation and pull-down assays
For immunoprecipitation, cells were lysed in NP-40 buffer (10 mM Tris, pH 7.4, 1 mM EDTA, 1 mM EGTA, 50 mM NaCl, and 0.5% NP-40), incubated at 4°C for 30 min, and spun at 36,000 rpm for 30 min. Supernatants were precleared with protein G beads and normal mouse IgG for 30 min at 4°C. After preclearing, lysates were incubated with antibody or normal mouse IgG for 2 h. Protein G beads were added for an additional 2 h. Complexes were washed in NP-40 buffer three times, eluted in 2 x SDS buffer, and loaded in SDSpolyacrylamide gels. For -catenin immunoprecipitation, both monoclonal and polyclonal antibodies were used. For immunofluorescence and blotting, monoclonal
-catenin antibody was used.
GSTcortactin and GSTCTcortactin were expressed in Escherichia coli and purified in glutathione-sepharose beads (Amersham Biosciences) by standard methods. Cell lysates in NP-40 buffer were incubated with GST fusion proteins bound to glutathione sepharose beads at 4°C for 30 min and washed three times in NP-40 buffer. Beads were resuspended in 2 x SDS buffer and loaded for SDS-PAGE.
Morphometry
The length of a particular process was measured by tracing a line from the cell body to the end of the process with MetaMorph software. In the PC12 cells, primary processes were defined as those emerging from the cell body. Secondary processes emerged from primary processes and were longer than 1.5 µm. Three independent experiments were quantified in all cases.
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Acknowledgments |
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This study was supported by the National Institutes of Health and the March of Dimes.
Submitted: 6 November 2003
Revised: 28 April 2003
Accepted: 13 May 2003
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References |
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