Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA
*Author for correspondence (e-mail: anton.Bennett{at}yale.edu)
Accepted March 13, 2001
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SUMMARY |
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Key words: SHP-2, Tyrosine phosphatase, Myogenesis, Signalling, Myoblast, SHPS-1
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INTRODUCTION |
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We have focused on determining whether SHP-2, an Src homology 2 (SH2) domain-containing PTP, which is expressed ubiquitously and is highly abundant in skeletal muscle, is involved in myogenesis (Adachi et al., 1992; Ahmad et al., 1993; Feng et al., 1993; Freeman et al., 1992; Vogel et al., 1993). Studies in Drosophila (Perkins et al., 1992), Xenopus (Tang et al., 1995), C. elegans (Gutch et al., 1998) and mice (Saxton et al., 1997) demonstrate that SHP-2 is required for development. The PTP activity of SHP-2 mediates positive signaling (growth and differentiation promoting) and functions either upstream of, and/or parallel to, Ras in the Raf/MEK/Erk pathway (Neel, 1993; Neel and Tonks, 1997; Tonks and Neel, 1996). In addition to signaling to the Erks, SHP-2 plays an important role in cell migration/motility, morphogenesis and cell spreading via integrin-dependent mechanisms (OReilly et al., 2000; Oh et al., 1999; Tsuda et al., 1998; Yu et al., 1998).
In most cases, if not all, SHP-2 propagates its downstream signal(s) by first interacting via its SH2 domains with tyrosyl-phosphorylated proteins. This event serves both to localize and to activate SHP-2, and ensures that the target of SHP-2 is appropriately activated in a coordinated and specific manner. To begin defining the role of SHP-2 in skeletal muscle differentiation, we have attempted to identify proteins with which it may interact during myogenesis. Such interacting proteins will likely dictate how and when SHP-2 is activated during myogenesis. The SH2 domains of SHP-2 mediate its direct interaction with the activated platelet-derived growth factor (PDGF) receptor ß (Lechleider et al., 1993) as well as multi-substrate adapter proteins such as IRS-1 (Kuhné et al., 1993), Gab-1 (Holado-Madruga et al., 1997) Gab-2 (Gu et al., 1998; Zhao et al., 1999a), FRS-2/SNT-1, SNT-2 (Kouhara et al., 1997; Xu et al., 1998) and DOS (Herbst et al., 1996; Raabe et al., 1996). SHP-2 also interacts with transmembrane glycoproteins, such as the signal regulatory proteins (SIRPs) (Kharitonenkov et al., 1997) (also known as SHP-2 substrate-1 (SHPS-1) (Fujioka et al., 1996), brain-immunoglobulin like molecule (BIT) (Sano et al., 1997), p84 (Comu et al., 1997) and macrophage fusion receptor (MFR) (Saginario et al., 1998) and the platelet/endothelial cell adhesion molecule (PECAM) (Jackson et al., 1997; Sagawa et al., 1997). The basis for how and when SHP-2 participates in cell-type and growth factor-specific signaling is likely regulated by the mutually exclusive complement of protein-protein interactions that SHP-2 forms. We have identified that SHP-2 interacts with Grb-2-associated binder-1 (Gab-1) and SHPS-1 in the C2C12 myoblast cell line. We show that SHPS-1/SHP-2 complex formation is an integral signaling event during C2C12 myoblast differentiation, suggesting a functional link between SHP-2 and myogenic progression.
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MATERIALS AND METHODS |
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Immunoprecipitation and immunoblotting
SHPS-1 and Gab-1 polyclonal antibodies were purchased from Upstate Biotechnology (Lake Placid, NY, USA). SHPS-1 polyclonal antibodies were also provided by Dr Benjamin Neel (Beth Israel Deaconess Hospital, Boston, MA, USA). Anti-SIRP-1/MFR (10C4) monoclonal antibodies were provided by Dr Agnes Vignery (Yale University School of Medicine, New Haven, CT, USA) (Saginario et al., 1995). SHP-2 polyclonal antibodies used for immunoprecipitation experiments were obtained from Gen-Shen Feng (Burnham Institute, La Jolla, CA, USA) or were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA). SHP-2 immunoblots were performed using a monoclonal antibody purchased from Transduction Laboratories (Lexington, KY, USA). Dr Peter Houghton (St Jude Childrens Research Hospital, Memphis, TN, USA) provided antibodies to MyoD. Anti-phosphotyrosine immunoblots were carried out using the 4G10 antibody purchased from Upstate Biotechnology and myosin heavy chain antibodies (MF20) were purchased from the Developmental Studies Hybridoma Bank (University of Iowa, Iowa City, IA, USA). Phospho-specific antibodies to Akt and MAPK were obtained from New England Biolabs (Beverley, MA, USA). Anti-Akt antibodies were purchased from Santa Cruz Biotechnology and anti-MAPK (C1) antibodies were a kind gift from John Blenis (Harvard Medical School, Boston, MA, USA). Insulin-like growth factor-I and II, and SB203580 were purchased from Calbiochem (La Jolla, CA, USA). All other chemicals were purchased from Sigma.
Immunoprecipitation and immunoblotting experiments were performed by lysing cells on ice in 1 ml of NP-40 lysis buffer containing 1.0% NP-40, 5 µg/ml leupeptin, 5 µg/ml aprotinin, 1 µg/ml pepstatin A, 1 mM phenylmethylsulfonyl fluoride, 1 mM benzamidine and 0.2 mM sodium orthovanadate. Lysates were centrifuged at 14,000 r.p.m. for 15 minutes at 4°C and supernatants were precleared for 15 minutes with 2 µl Pansorbin (Calbiochem-Novabiochem, La Jolla, CA, USA). Protein concentration was determined using the Bradford Assay (Pierce, Rockford, IL, USA). Approximately 0.5-1.0 mg of total cell lysates was used for each immunoprecipitation and approximately 50 µg of total cell lysates were used for immunoblotting. Immunoprecipitation experiments were carried out overnight at 4°C. For immunoprecipitation experiments, 6 µg of SHP-2 antibodies, 10 µg SHPS-1 antibodies, 15 µg of Gab-1 antibodies were used to immunoprecipitate the respective proteins. Immune complexes were collected on Protein A-sepharose beads, which were washed three times with lysis buffer containing 0.1 mM sodium orthovanadate, with a final wash in STE (150 mM NaCl, 20 mM Tris, pH 7.4, and 5 mM EDTA) plus 0.2 mM sodium orthovanadate. Immune complexes were resolved by SDS-PAGE and transferred onto Immobilon-P membranes (Millipore, Bedford, MA, USA). Immobilon-P membranes were washed three times for 10 minutes in TBST (20 mM Tris-HCl, pH 8.0, 150 mM NaCl and 0.05% Tween-20) and were blocked for at least 1 hour with 5% non-fat dry milk in TBST at 4°C. Immunoblots that were incubated with anti-phosphotyrosine 4G10 antibodies (pTyr) were blocked for at least 1 hour in 5% BSA (Boehringer-Mannheim, Indianapolis, IN, USA) in TBST. After blocking, membranes were washed three times for 10 minutes in TBST. Membranes were then incubated with primary antibodies (anti-SHP-2 at 1:1,000; anti-SHPS-1 at 1:5,000; anti-myosin heavy chain antibody at 1:12; anti-Gab-1 at 1:1,000; anti-MyoD at 1:1,000; anti-Akt at 1:1,000; and anti-myogenin at 1:12) diluted in 2.5% non-fat dry milk, for 2-4 hours at 4°C. Anti-phosphotyrosine 4G10 antibodies were diluted to 1:2,000 in 2.5% BSA/TBST and anti-phospho-MAPK and anti-phospho-Akt antibodies were diluted to 1:1,000 in 2.5% nonfat dry milk/TBST. Primary antibodies were incubated with membranes for either 3 hours at room temperature or overnight at 4°C. Following incubation with primary antibodies, membranes were washed three times for 10 minutes in TBST and primary antibodies were detected with either anti-rabbit or anti-mouse horseradish peroxidase-conjugated antibodies at a 1:5,000 dilution in TBST for 30 minutes. Membranes were washed and primary antibodies visualized using enhanced chemiluminescence detection (Amersham Pharmacia Biotech, Piscataway, NJ, USA).
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RESULTS |
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Induction of SHPS-1 protein expression, tyrosyl phosphorylation and association with SHP-2 during C2C12 myogenesis
We next examined the protein expression and tyrosyl phosphorylation of SHPS-1 during myogenic differentiation. Early on during C2C12 myogenesis, the expression of SHPS-1 increases and plateaus by 48 hours into differentiation (Fig. 3B). In order to determine the kinetics of SHPS-1 tyrosyl phosphorylation, SHPS-1 was immunoprecipitated at various times during myogenic differentiation. These immune complexes were immunoblotted with anti-phosphotyrosine antibodies. In addition, SHP-2 was immunoprecipitated from these lysates and immune complexes were immunoblotted with anti-SHPS-1 antibodies. We found that SHPS-1 is basally tyrosyl-phosphorylated, and forms a complex with SHP-2 in undifferentiated myoblasts (Fig. 3C,D, top). Upon initiation of myogenesis, SHPS-1 becomes tyrosyl-phosphorylated between 12 and 24 hours into differentiation (Fig. 3C, top), which correlates with an increase in the level of SHPS-1 in SHP-2 immune complexes (Fig. 3D, top). The level of tyrosyl phosphorylation on SHPS-1 peaks at 48 hours and declines slightly by 72 hours as myoblasts undergo fusion to form multinucleated myotubes (Fig. 3C, top). These data demonstrate that SHPS-1 undergoes an increase in protein expression, becomes tyrosyl-phosphorylated and associates with SHP-2 during C2C12 myogenesis.
SHP-2 interacting p120 tyrosyl-phosphorylated protein is a complex that also contains Gab-1
SHPS-1 is a glycoprotein containing 15 N-glycosylation sites. Upon treatment of SHP-2 immune complexes with endoglycosidase F, SHPS-1 can be deglycosylated, resulting in the generation of a core protein of an approximate molecular mass 60 kDa (Fujioka et al., 1996; Kharitonenkov et al., 1997; Saginario et al., 1995). Our experiments indicate that although SHPS-1 could be deglycoslyated to its 60 kDa core protein, we were unable to reduce completely the mass of the p120 complex to a lower core molecular mass (data not shown). These results suggest that other non-glycosylated tyrosyl-phosphorylated protein(s) might also constitute a component of the p120 complex that associates with SHP-2. Gab-1 is a tyrosyl-phosphorylated multi-substrate docking protein of 120 kDa that binds SH2 domain-containing proteins such as PI-3 kinase, Grb2 and SHP-2. Therefore, we tested whether the p120 complex also contains Gab-1. In Fig. 4A, we show that when lysates from undifferentiated C2C12 myoblasts are subjected to immunoprecipitation with anti-SHP-2 antibodies, the immune complexes contain a protein that is recognized in an immune-specific manner by antibodies to Gab-1. These data indicate that in undifferentiated C2C12 myoblasts, SHP-2 also forms a complex with Gab-1.
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MyoD induces the association of SHPS-1 and SHP-2 in 10T fibroblasts
The data presented in Fig. 3 indicate that the induction of SHPS-1 tyrosyl phosphorylation and association with SHP-2 correlates with the progression of myogenesis. In contrast, Gab-1 tyrosyl phosphorylation and association with SHP-2 does not (Fig. 4). We hypothesized that the initiation and subsequent progression of myogenesis in C2C12 myoblasts induces tyrosyl phosphorylation of SHPS-1 and subsequently its association with SHP-2. To test this, we compared SHP-2 complex formation with SHPS-1 in 10T fibroblasts and 10T
fibroblasts that were converted to the myogenic lineage by stable expression of MyoD (10T
-MyoD). In Fig. 5A, SHP-2 was immunoprecipitated from 10T
and 10T
-MyoD fibroblasts; the resultant immune complexes were immunoblotted with anti-phosphotyrosine antibodies. In 10T
-MyoD fibroblasts, we observed a dramatic increase in the amount of both p120 and p180 tyrosyl-phosphorylated proteins associated with SHP-2, as well as an increase in the levels of tyrosyl-phosphorylated SHP-2, as compared to 10T
fibroblasts (Fig. 5A). Importantly, the levels of SHP-2 that were immunoprecipitated between 10T
and 10T
-MyoD fibroblasts were equivalent (Fig. 5A, bottom panel), as was the total amount of SHPS-1 protein between these two cell lines (Fig. 5B). In addition, SHP-2 immune complexes also contained higher levels of SHPS-1 in 10T
-MyoD as compared to 10T
fibroblasts (Fig. 5C). This was consistent with the observation that SHPS-1 itself was hypertyrosyl-phosphorylated in 10T
-MyoD fibroblasts as compared to 10T
fibroblasts (Fig. 5D). These data demonstrate that the initiation of the muscle differentiation program in fibroblasts, by the expression of MyoD, is sufficient to induce SHPS-1/SHP-2 complex formation.
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DISCUSSION |
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SHP-2 is highly abundant in skeletal muscle and may play an important role in muscle development and/or post-developmental muscle function. Our observation that the expression of SHP-2 is induced during the initial periods of differentiation, concomitant with that of MyoD and myogenin induction (Fig. 1), is consistent with data from Mei et al. (1996). This group showed that SHP-2 is induced in differentiating myoblasts prepared from both embryonic mouse limbs and in developing rat muscle in vivo (Mei et al., 1996). In addition to SHP-2 becoming upregulated, the levels of SHPS-1 protein expression and tyrosyl phosphorylation increase during C2C12 differentiation (Figs 3 and 7). This correlates with an increase in the level of SHPS-1 that associates with SHP-2. Originally identified as a hypertyrosyl-phosphorylated protein in fibroblasts overexpressing a catalytically inactive mutant of SHP-2, SHPS-1 has been shown to bind and serve as a substrate for SHP-2 (Fujioka et al., 1996; Timms et al., 1998). The extracellular domain of SHPS-1 contains three Ig domains and a cytoplasmic domain comprising four tyrosyl-phosphorylation sites. Two of these tyrosyl residues are in the sequence context that describes an immunoreceptor tyrosine-based inhibitory motif (ITIM; I/V-X-pY-X-X-L/V/I). These ITIMs bind the SH2 domains of both SHP-2, and its related hematopoietic counterpart SHP-1 (Fujioka et al., 1996; Kharitonenkov et al., 1997; Saginario et al., 1998). SHPS-1 becomes tyrosyl-phosphorylated in response to a variety of growth factors and by integrin-mediated cell adhesion (Fujioka et al., 1996; Kharitonenkov et al., 1997; Ochi et al., 1997; Oh et al., 1999; Takeda et al., 1998; Tsuda et al., 1998). SHPS-1 is suggested to be involved in positive (Fujioka et al., 1996) and negative (Inagaki et al., 2000; Kharitonenkov et al., 1997) growth factor signaling, integrin-mediated signaling (Fujioka et al., 1996; Oh et al., 1999; Tsuda et al., 1998), neurite outgrowth (Abosch and Lagenaur, 1993), inhibition of IgE-induced mast cell activation (Lienard et al., 1999) and macrophage multinucleation (Saginario et al., 1995; Saginario et al., 1998). The functional consequences of SHPS-1 induction in expression, and tyrosyl phosphorylation during differentiation of C2C12 myoblasts, remain to be determined.
In addition to the p180 tyrosyl-phosphorylated protein (Fig. 2), which remains to be identified, we found that SHP-2 forms a complex with Gab-1 in C2C12 myoblasts (Fig. 4). Gab-1 tyrosyl-phosphorylation levels do not change when myoblasts are induced to differentiate (Fig. 3), or if MyoD is activated in the MyoD-ER 10T cells (Fig. 6). However, as myotubes form, Gab-1 undergoes tyrosyl dephosphorylation (Fig. 3), concomitant with that of tyrosyl dephosphorylation of SHP-2 (Fig. 2). Interestingly, we found that the amount of Gab-1 in SHP-2 immune complexes remains unchanged even when Gab-1 becomes dephosphorylated in terminally differentiated multinucleated myotubes (Fig. 4). Three possibilities can be proposed to explain this result. First, it is possible that SHP-2 interacts with Gab-1 in a non-phosphotyrosyl-dependent manner. Second, in myoblasts, SHP-2 could interact indirectly with Gab-1 via a third component. Finally, SHP-2 may interact directly with Gab-1 (Lehr et al., 1999), while SHP-2 and/or other PTPs dephosphorylate Gab-1 at sites other than those with which SHP-2 interacts. Since the level of Gab-1 protein during myogenesis remains constant (Fig. 4), the reduced levels of tyrosyl phosphorylation on Gab-1 during myogenesis are likely catalyzed through the actions of a PTP. There is both genetic and biochemical evidence implicating Gab-1 as an SHP-2 substrate (Herbst et al., 1996; Nishida et al., 1999; Raabe et al., 1996). Gab-1 mediates branching tubulogenesis in epithelial cells (Maroun et al., 1999; Weidner et al., 1996), and may also be involved in similar processes such as branching and/or multinucleation in myoblasts.
The most striking observation of this study is the result that tyrosyl phosphorylation of SHPS-1 and subsequently SHPS-1/SHP-2 complex formation are integral processes of the differentiation of C2C12 myoblasts (Figs 5-7). Three lines of evidence support this conclusion: (1) SHPS-1/SHP-2 association correlates with the induction of MyoD during differentiation (Figs 1 and 3); (2) constitutive expression and inducible activation of MyoD in fibroblasts result in SHPS-1 tyrosyl phosphorylation and association with SHP-2 (Figs 5 and 6) and (3) inhibition of p38 MAPK activity by SB203580 in C2C12 myoblasts blocks SHPS-1 tyrosyl phosphorylation and its association with SHP-2 (Fig. 7). Previous studies from several groups have shown that p38 MAPK is required for skeletal muscle differentiation. (Cuenda and Cohen, 1999; Han et al., 1997; Zetser et al., 1999; Zhao et al., 1999b). Our results support these observations, and further demonstrate that the interaction between SHPS-1 and SHP-2 is also dependent upon p38 MAPK activity in C2C12 myoblasts. As SHP-2 is recruited to SHPS-1 during differentiation, it may subsequently participate in multiple signaling pathways during myogenesis. For example, SHP-2 has been implicated in regulating cell adhesion and cell motility, which are important components of the myogenic process. Indeed, if SHPS-1/SHP-2 complex formation functions downstream of MyoD, then it is reasonable to propose that this complex initiates signaling events which occur in concert with muscle-specific gene expression during myogenesis. It is clear that a substantial amount of work is needed in order to uncover the precise role(s) that SHP-2 plays in skeletal muscle differentiation.
How does SHPS-1 become tyrosyl-phosphorylated during C2C12 differentiation? Several candidate autocrine growth factors that promote myogenesis have been identified. These include primarily the insulin-like growth factors (IGFs) (Florini et al., 1996; Florini et al., 1993). Moreover, a positive relationship between muscle-specific gene expression and IGF production during myogenesis has been reported (Florini et al., 1991; Kou and Rotwein, 1993; Rosen et al., 1993; Stewart and Rotwein, 1996). Interestingly, neither insulin, IGF-I nor IGF-II induce tyrosyl phosphorylation of SHPS-1 in C2C12 myoblasts, despite the activation of both the Erk and PI-3K/Akt pathways (Fig. 8). These observations suggest that growth factors other than insulin/IGFs, and/or other signaling mechanisms regulate SHPS-1 tyrosyl phosphorylation in myoblasts. Consistent with the inability of the IGFs to stimulate SHPS-1 tyrosyl phosphorylation, IGF-I also fails to induce p38 MAPK activation in C2C12 myoblasts (Wu et al., 2000). It will be important to establish how SHPS-1 becomes tyrosyl-phosphorylated during C2C12 myogenesis; this information may also yield insight into how the p38 MAPK pathway is activated.
In summary, we have identified that during C2C12 myogenesis, SHP-2 forms a complex with SHPS-1 and Gab-1. We have found that SHP-2/SHPS-1 interactions are induced as a specific consequence of myogenic progression in C2C12 myoblasts. Further investigation is now underway to determine the functional role of SHP-2, in the context of its interactions with both Gab-1 and SHPS-1, in myoblast growth and differentiation.
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ACKNOWLEDGMENTS |
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