Article |
Correspondence to W. Birchmeier: wbirch{at}mdc-berlin.de
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Abstract |
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Abbreviations used in this paper: GDNF, glial cell line-derived neurotrophic factor; HGF/SF, hepatocyte growth factor/scatter factor; MEN, multiple endocrine neoplasia; PI3K, phosphatidylinositol-3-kinase; sGFR
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Introduction |
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The Ret receptor tyrosine kinase is crucial for development of enteric nervous system and mammalian kidney, as targeted deletion of Ret in mice leads to loss of enteric ganglia and severe kidney hypodysplasia or aplasia caused by a failure of ureteric bud outgrowth (Romeo et al., 1994; Schuchardt et al., 1994; Smith et al., 1994). Tubular outgrowth of the ureteric bud epithelium is regulated by signals emanating from surrounding metanephric mesenchyme (Saxen and Sariola, 1987; Sariola and Sainio, 1997), e.g., glial cell linederived neurotrophic factor (GDNF). GDNF activates Ret at the tips of ureteric bud epithelia (Sanchez et al., 1996; Enomoto et al., 1998; Baloh et al., 2000; Vainio and Lin, 2002), where Ret is expressed in two major splice variants, Ret9 and Ret51, which differ only in their COOH-terminal amino acids (Tahira et al., 1990). Ret9 is of particular importance for both kidney and enteric nervous system development, as severe kidney agenesis and loss of enteric ganglia of Ret-null mutant mice can be rescued through reexpression of Ret9, but not of Ret51 (Srinivas et al., 1999; de Graaff et al., 2001). Gain-of-function mutations of Ret in human patients are associated with various inherited cancer syndromes leading to neuroendocrine tumor formation, such as multiple endocrine neoplasia (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (Jhiang, 2000). Patients with MEN 2A and MEN 2B mutations also show renal dysplasia (Lore et al., 2000, 2001; McIntyre et al., 2003).
Activation of Ret by GDNF in the presence of its cognate coreceptor, GFR1, leads to autophosphorylation of tyrosine residues in the cytoplasmic domain of Ret and subsequent recruitment of signaling mediators such as PLC
and the adaptor proteins Grb2, Shc, FRS-2, and dok1-5 (Borrello et al., 1996; Arighi et al., 1997; Alberti et al., 1998; Grimm et al., 2001; Kurokawa et al., 2001). Grb2 can recruit Sos and signaling complexes mediated by the Gab adaptor proteins, containing the tyrosine phosphatase SHP-2 and phosphatidylinositol-3-kinase (PI3K; Hayashi et al., 2000). These adaptors interact with either of the two Ret isoforms. Binding of adaptor proteins to Ret9 and Ret51 leads to activation of the ErkMAPK and PI3K pathways (van Weering and Bos, 1998) as well as to cytoskeletal reorganization through activation of Rac (Fukuda et al., 2002). However, the signaling mechanisms that underlie the functional differences between Ret9 and Ret51 during embryonic development remained unclear.
We have here identified a new signaling complex of the Ret tyrosine kinase, involving the Shank family of neuronal adaptors. Complex formation depends on the direct interaction of the Shank3 PDZ domain with a novel PDZ-binding motif in the Ret9 isoform. This complex mediates tubulogenesis of kidney epithelial cells in vitro, which mimics ureteric bud branching during kidney development (Sachs et al., 1996; Pollack et al., 1998). By recruiting further signaling mediators, Shank3 induces sustained signaling by the ErkMAPK and PI3K pathways. Our findings reveal a novel function for Shank proteins in signal transduction of tyrosine kinase receptors, and provide a molecular mechanism for the divergent functions of Ret9 and Ret51.
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Results |
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To confirm that the ShankRet9 interaction is direct, we performed a PDZ class switch experiment (Kaech et al., 1998) by introducing compensatory mutations in Shank3 and Ret9. PDZ domains can be subdivided by their ability to bind to different receptor tails (Songyang et al., 1997; Vaccaro and Dente, 2002). Shank3 harbors a type I PDZ domain characterized by the presence of a histidine residue at position 716 (Fig. 2 a). Ret9 contains a type I PDZ-binding motif characterized by a threonine residue at position 1070. Mutation of the critical histidine residue to valine converts the Shank3 PDZ domain to a class II domain (Shank3PDZ HV), which no longer binds to Ret9 (Fig. 2 b). Introduction of a compensatory mutation in Ret9 (threonine 1070 to tyrosine, Ret9 TY) converts the PDZ-binding motif into a type IIbinding motif and reconstitutes the Shank3Ret9 interaction (Fig. 2 b). These data demonstrate that Ret9 and Shank3 interact in a PDZ domainmediated fashion, and that this interaction is direct.
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Shank3 interacts with the adaptor protein Grb2, which mediates sustained ErkMAPKand PI3K signaling and epithelial tube formation
Several adaptor molecules such as Shc, Grb2, FRS2, and dok4/5 are known to be involved in stimulation of the ErkMAPK pathway downstream of Ret and are recruited to the plasma membrane (Borrello et al., 1996; Arighi et al., 1997; Alberti et al., 1998; Grimm et al., 2001; Kurokawa et al., 2001). Analysis of the Shank3Pro2 sequence revealed a potential binding site for the Grb2 SH2 domain, with the consensus sequence pYXNX. Indeed, endogenous Grb2 was recruited to this binding site, as shown by coimmunoprecipitation of Shank3Pro2 upon coexpression of Ret9 (Fig. 7 b). Coexpression of the PDZ-binding motif mutant Ret9 FA did not allow binding of Grb2 to Shank3Pro2. Moreover, coexpression of Ret9 leads to significantly higher levels of Shank3 phosphorylation than Ret9 FA. We determined that Grb2 is not complexed indirectly with Ret9 through Shc, because Shank3Pro2 still binds Grb2 when the Shc-bindingdeficient Ret9 Y1062F mutant is coexpressed (Fig. 7, a and b). Finally, we mutated tyrosine 1006 to phenylalanine in the Grb2-binding site of Shank3 (Shank3Pro1 Y1006F), which does not interact with Grb2 (Fig. 7, a and b).
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Discussion |
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Originally identified in neuronal cells (Boeckers et al., 1999; Naisbitt et al., 1999; Tu et al., 1999; Yao et al., 1999), Shank proteins are also expressed in other tissues such as in epithelial ducts of lung, pancreas, and kidney, and in hepatic bile ducts (Redecker et al., 2001). In neuronal cells, Shank proteins localize to postsynaptic densities and have been previously shown to regulate dendritic spine morphology by linking the postsynaptic signaling machinery to the cortical cytoskeleton (Naisbitt et al., 1999; Tu et al., 1999; Sheng and Kim, 2000; Sala et al., 2001; Boeckers et al., 2002). We demonstrate here that Shank3 also has a defined biological role outside of neuronal tissues, and that Shank3 actively participates in signal transduction. Shank3 thus provides a platform for the regulated recruitment of additional effectors, such as Grb2, that are involved in stimulation of downstream signaling, although Shank3 may still be involved in integration of receptor complexes with the cytoskeleton. Other receptor tyrosine kinases, for instance ErbB2, have been shown to harbor PDZ-binding motifs, which interact with scaffold proteins (Maudsley et al., 2000; Shelly et al., 2003). The PDZ protein ERBIN was described initially to be important for the correct cellular localization of ErbB2, but is now also known to participate in downstream signaling (Borg et al., 2000; Huang et al., 2003).
The kinetics of activation of the ErkMAPK and PI3K pathways is crucial for determining the biological outcome of receptor tyrosine kinase signaling, e.g., increased migration and differentiation of epithelial cells. From studies of the Met receptor, it is known that sustained activation of ErkMAPK and PI3K signaling pathways is required for tubule formation, whereas transient activation of these pathways is insufficient to induce such morphological alterations (for review see Rosario and Birchmeier, 2003). We show here that Shank3 function is required for sustained activation of both ErkMAPK and PI3K pathways downstream of Ret9. The central region of Shank3 (aa 6321057) is sufficient to mediate sustained activation of the ErkMAPK and PI3K pathways and epithelial tubule formation, and a newly identified Grb2-binding site on Shank3 is essential for this activity. Interaction between Shank3 and Grb2 is SH2 domain mediated and requires phosphorylation by Ret9. In contrast, binding of Grb2 to Ret9 through Shc or to Ret51 through an additional Grb2-binding site (Besset et al., 2000) does not induce sustained activation of the downstream pathways. Thus, Shank3 acts as a true scaffolding adaptor, which amplifies receptor tyrosine kinase signaling. Shank-associated Grb2 may recruit Gab1 and Shp-2, which are essential in tube formation (Maroun et al., 2000; Schaeper et al., 2000; Rosario and Birchmeier, 2003). Shank proteins may also serve to recruit additional signaling effectors through the proline-rich and other tyrosine-containing sequences in the central domain. The biological functions of these sites have not been determined. Shank3 is thus the first isoform-specific Ret signaling effector. The isoform specificity of the RetShank interaction provides a molecular explanation for the crucial role of Ret9 during mammalian kidney development. Moreover, the Shank-binding site is conserved in the RetPTC2 fusion protein found in human patients with papillary thyroid carcinomas (Bongarzone et al., 1993), and Shank proteins may therefore also be involved in the development of Ret-induced tumors.
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Materials and methods |
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Immunofluorescence and cell culture
Mouse embryos were dissected and fixed overnight in 4% formaldehyde. For frozen sections, fixed embryos were rinsed with PBS, and embedded in water soluble glycol's and resins compound (Tissue-Tek O.C.T. compound; Sakura Finetek). After acetone postfixation, sections were labeled using anti-Shank3 antibody. Pictures were taken with a Zeiss Axiophot fluorescence microscope using Zeiss 40x F Fluar optics and a Diagnostic Instruments SPOT-RT-Monochrome CCD camera. Contrast was adjusted using Adobe Photoshop imaging software.
MDCK cell lines were maintained in DMEM supplemented with 10% FCS, 100 IU/ml penicillin, and 100 mg/ml streptomycin at 37°C in 5% CO2. To generate stable MDCK cell lines, cells were transfected with Lipofectamine 2000 (Invitrogen) and selected with 120 µg/ml G418 or 1.25 µg/ml Puromycin. HEK293 (human embryonic kidney 293) cells and Neuro2A (mouse neuroblastoma 2A) cells were maintained in DMEM, 10% FCS as for the MDCK cells, and transfected using the calcium phosphate method. In the tubulogenesis assay, single MDCK cells were embedded in a collagen type I solution containing 1.5 mg/ml Vitrogen 100 (Nutacon BV), 10% 10x DMEM (Invitrogen), 10% FCS, 2.2 mg ml NaHCO3, and 20 mM Hepes, pH 7.6. After gelation, medium was added and cells were grown for 35 d until they formed cysts. Cells were stimulated with GDNF and sGFR1, or HGF/SF, and grown for 57 d further before fixation in 4% formaldehyde. Pictures were taken with a Zeiss Axiovert 135 microscope, using Zeiss 10x Achroplan optics and a Jenoptik ProgRes 3012mf camera. Pictures were deconvoluted manually by stacking several images of different focus layers and reducing nonfocused regions. Contrast was adjusted using Adobe Photoshop imaging software.
Submitted: 19 April 2004
Accepted: 25 October 2004
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References |
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