- Email: [email protected]
Feedback inhibitors of the epidermal growth factor receptor signaling pathways
The International Journal of Biochemistry & Cell Biology 41 (2009) 511–515
Contents lists available at ScienceDirect
The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel
Signaling network in focus
Feedback inhibitors of the epidermal growth factor receptor signaling pathways Noriko Gotoh ∗ Division of Systems Biomedical Technology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 11 April 2008 Received in revised form 26 June 2008 Accepted 30 June 2008 Available online 9 August 2008 Keywords: Mig-6 RALT Gene 33 FRS2 SNT-2 FRS3 SOCS LRIG Ubiquitinylation Biomarker Cancer EGF ErbB HER
a b s t r a c t The epidermal growth factor receptor family tyrosine kinases transduce signals for cell proliferation and migration and contribute to tumorigenesis. A recent extensive research has highlighted the major roles of the negative regulators of complex epidermal growth factor receptor signaling networks. These regulators fine-tune signaling under physiological conditions. When their expression is downregulated, the resultant aberrant epidermal growth factor receptor signaling may promote cell proliferation and migration, leading to increased tumorigenesis. In this paper, I review specific feedback inhibitors that target epidermal growth factor receptors preferentially, via multiple modes of action. The inhibitors include mitogen-inducible gene-6 (Mig-6)/receptor-associated late transducer (RALT)/Gene 33, fibroblast growth factor receptor substrate 2 (FRS2)/suc1-associated neurotrophic factor target-2 (SNT-2)/FRS3, suppressor of cytokine signaling 3 (SOCS3)/SOCS4/SOCS5, and leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1). Although only fragmentary evidence is available regarding these inhibitors, they might be useful as cancer biomarkers, and the development of drugs that target them would certainly advance personalized medicine in the near future. © 2008 Elsevier Ltd. All rights reserved.
1. Introduction Signal transduction pathways via receptor tyrosine kinases (RTKs) play pivotal roles in numerous aspects of physiological and pathological biology. The epidermal growth factor receptor (EGFR) family, in particular, has been studied extensively as a prototype of RTKs since the 1980s (Citri and Yarden, 2006). It comprises the following 4 members: EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. These receptors homo- and heterodimerize, activating considerably complex signaling networks, and ultimately induce strong signals for cell proliferation and migration. There is sufficient evidence regarding the involvement of the abovementioned receptors in various cancer malignancies. The EGFR family members and their ligands are overexpressed in many types of cancers. Although less frequently, structural mutations occur in their ligand-binding domains, consequent to which these receptors constitutively dimerize and get activated. In contrast to the
∗ Tel.: +81 3 5449 5629; fax: +81 3 5449 5425. E-mail address: [email protected]. 1357-2725/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2008.06.019
aberrant EGFR signaling under disease conditions such as cancer, signaling networks should be coordinated in a fine-tuned manner under physiological conditions. In the past decade, understanding of the direct participation of negative regulators in RTK signaling networks has enhanced considerably (Sweeney and Carraway, 2004). Emerging evidences indicate that there exist many negative regulators and that these regulators actually play major roles in regulating signaling networks via multiple modes of action. The coordinated actions of both positive and negative regulators qualitatively and quantitatively fine-tune signaling under physiological conditions. Further, it has been recognized that a loss of or decrease in the expression of negative regulators is related to cancer malignancy. There are certain general negative regulators/inhibitors of RTK signaling pathways. For example, Cbl – an E3 ubiquitin ligase – induces ubiquitinylation and degradation of signaling molecules that are activated by a variety of stimuli (Dikic and Giordano, 2003; Kirisits et al., 2007). In this review, I summarize the currently available information regarding the relatively specific negative regulators/inhibitors that preferentially target the EGFR family members.
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Signaling network facts • Mitogen-inducible gene 6 (Mig-6)/receptor-associated late transducer (RALT)/Gene 33 is an early-response gene induced by epidermal growth factor (EGF). Mig-6/RALT acts as a negative feedback regulator of EGF receptor (EGFR). Its transcription is induced by the extracellular signal-regulated kinase (ERK) pathway that is activated by growth factors such as EGF or by multiple stimuli, including osmotic and mechanical stress. Mig-6/RALT/Gene 33 binds to the tyrosine kinase (TK) domains of EGFR and ErbB2 and inhibits the TK activity. • Fibroblast growth factor receptor substrate 2 beta (FRS2), also termed suc1-associated neurotrophic factor target-2 (SNT-2) and FRS3, constitutively binds to EGFR, regardless of ligand stimulation. After activation of ERK by various growth factors, including EGF, the phosphorylated ERK binds to FRS2 and inhibits EGFR autophosphorylation and signal transduction. Thus, FRS2 acts as a negative feedback regulator of EGFR. • Suppressor of cytokine signaling 3 (SOCS3)/SOCS4/SOCS5 is an early-response gene induced by EGF. SOCS proteins are negative feedback regulators of EGFR. They bind to autophosphorylated EGFR via their Src homology 2 (SH2) domains and recruit E3 ubiquitin ligase complex via their SOCS domains, leading to the ubiquitinylation and degradation of EGFR. • Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is an early-response gene induced by EGF. LRIG1 acts as a negative feedback regulator of EGFR. It binds to EGFR via its extracellular domain and recruits Cbl – an E3 ubiquitin ligase – via its cytoplasmic domain, leading to the ubiquitinylation and degradation of EGFR.
2. Key molecules, cascades, and functions 2.1. Mig-6/RALT/Gene 33 Mig-6/RALT is a multiadaptor protein that has many interactive domains (Fig. 1). Mig-6 was originally identified as an immediate early-response gene induced by stimulation with fetal calf serum, insulin, and growth factors, including EGF. Transcription of Mig-6 is induced by an array of extracellular stimuli, including osmotic stress and mechanical stress (Makkinje et al., 2000). On the other hand, yeast two-hybrid screening performed using ErbB2 containing the TK domain as bait also identified Mig-6 that was renamed RALT (Fiorentino et al., 2000). Mig-6/RALT binds to all EGFR family members via its ErbB2binding domain and inhibits the TK activity (Anastasi et al., 2003) (Fig. 2A). The binding between Mig-6/RALT and the EGFR family TKs occurs only after ligand activation. Since the ErbB2-binding domain specifically interacts with the TK domain of EGFR and ErbB2, Mig6/RALT acts as a specific inhibitor of signaling via the EGFR family TKs. Signals for the induction of Mig-6/RALT expression by various stimuli are transduced via the Ras/ERK pathway. Since the EGFR family TKs strongly activate this pathway, Mig-6/RALT serves as a feedback inhibitor. Recently, the crystal structure of a complex between the EGFR TK domain and a fragment of the ErbB2-binding domain of Mig6/RALT was resolved (Zhang et al., 2007a). Before activation, the EGFR TK domain has an autoinhibited conformation that resembles that of inactive cyclin-dependent kinases (CDKs). Conversion to the active form requires interactions between the distal surface of the carboxy-terminal lobe (C lobe) of 1 kinase domain and the amino-terminal lobe of the other kinase domain in the asym-
metric activating dimer. The amino-terminal of the ErbB2-binding domain fragment of Mig-6/RALT binds to the distal surface of the C lobe of the EGFR TK domain. Therefore, Mig-6/RALT-mediated inhibition of the TK activity is due to the blockade of the dimer’s interface. Further, Mig-6/RALT is involved in signaling by other modes via its Cdc42/Rac interaction and binding (CRIB) domain. Mig-6/RALT binds to the GTP-bound form of Cdc42 via the CRIB domain and activates stress-activated protein kinase (SAPK) (Makkinje et al., 2000). It has been reported that the binding of Mig-6/RALT to Cdc42 inhibits the activity of Cdc42, resulting in the inhibition of hepatocyte growth factor (HGF)-induced cell migration (Pante et al., 2005). It is also reported that limited proteolytic processing yields the NH2 -terminal fragment of Mig-6/RALT containing the CRIB domain. The processed CRIB domain of Mig-6/RALT binds to inhibitory B␣ (IB␣) and competes with nuclear factor B (NFB), which is a binding partner of IB␣ in the inactive state, resulting in the activation of NFB (Tsunoda et al., 2002). 2.2. FRS2ˇ FRS2, also termed SNT-2 or FRS3, belongs to the FRS2 family of docking/scaffold adaptor proteins. This family comprises 2 members, FRS2␣ and FRS2, in mammals (Gotoh, 2008). Both members contain N-terminal myristylation sites for distribution on plasma membrane and a phosphotyrosine-binding (PTB) domain for binding to a limited number of RTK species, including fibroblast growth factor (FGF) receptor and nerve growth factor (NGF) receptor (Fig. 1). The activation of these RTKs enables phosphorylation of FRS2 at tyrosine residues and its subsequent binding to Grb2 and Shp2, an SH2 domain-containing adaptor protein and a tyrosine phosphatase, respectively. Subsequently, Shp2 activates the Ras/ERK pathway and Grb2 activates the Ras/ERK, phosphatidylinositol (PI) 3-kinase, and ubiquitinylation/degradation pathways by binding to Son of sevenless (SOS), Grb2-associated binder 1 (Gab1) and Cbl, respectively, via the Src homology 3 (SH3) domains of Grb2. FRS2␣ acts as “a conning center” in FGF signaling. In fact, genetically engineered FRS2␣ mutant mice exhibit a variety of phe-
Fig. 1. Schematic structures of the inhibitors of the epidermal growth factor receptor (EGFR) family members. In Mig-6/RALT, the proline-rich sequence binds to the Src homology 3 (SH3) domain of Grb2, the 14–3-3 binding domain (BD) binds to 14–33, and the ErbB2-binding domain (EBD) binds to the ErbB2 tyrosine kinase (TK) domain. The AH domain (AHD) is homologous to the Ack TK. The PTB domain of FRS2 binds to a phosphorylated tyrosine (Y) residue of the NGF receptor or the unphosphorylated juxtamembrane region of the FGF receptor. SP, signal peptide; LRR, leucine-rich repeats; Ig, immunoglobulin-like domain; TM, transmembrane domain.
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Fig. 2. Multiple modes of action of the inhibitors. (A) Mig-6/RALT transcription is induced by the activation of ERK pathway via activated EGFR or other stimuli. The translated Mig-6/RALT binds to the activated TK domain of EGFR and ErbB2 and inhibits the TK activity. (B) FRS2 constitutively binds to EGFR. Activated EGFR or other stimuli activate the ERK pathway. The activated ERK binds to FRS2 and inhibits the EGFR signaling. (C) SOCS3, SOCS4, or SOCS5 transcription is induced by stimulation with EGF. The translated SOCS3/SOCS4/SOCS5 binds to the autophosphorylated EGFR via its SH2 domain and recruits the E3 ubiquitin ligase complex via its SOCS box. (D) LRIG1 transcription is induced by stimulation with EGF. The translated LRIG1 binds to EGFR family members via its extracellular domain and recruits Cbl E3 ubiquitin ligase to its cytoplasmic tail, inducing ubiquitinylation/degradation of the EGFR family members.
notypes due to defects in FGF signaling in vivo (Gotoh et al., 2004a, 2005; Yamamoto et al., 2005). In contrast to the well-known functions of FRS2␣, the functions of FRS2 have long been unclear. FRS2 compensates for the loss of FRS2␣ and activates ERK in Frs2˛−/− mouse embryonic fibroblasts (MEFs) in response to FGF (Gotoh et al., 2004b). However, FRS2␣, but not FRS2, potentiates neurite outgrowth in PC12 cells in response to NGF, indicating that FRS2␣ and FRS2 are not completely redundant (Dixon et al., 2006). It has recently been unraveled that FRS2 plays a novel role of inhibiting EGF signaling. This was evident from the finding that FRS2 expression inhibits EGF-induced cell proliferation and transformation (Huang et al., 2006). The PTB domain of FRS2 constitutively binds to EGFRs, regardless of the absence or presence of ligands; however, FRS2 does not get phosphorylated at tyrosine residues by EGFR TK. Instead, it inhibits EGFR autophosphorylation, resulting in the inhibition of its downstream signaling (Fig. 2B). In contrast, FRS2␣ is phosphorylated at tyrosine residues by EGFR TK in cells where EGFRs are overexpressed. Therefore, FRS2 is a unique scaffolding adaptor that serves both as a negative and a positive regulator for receptor species-dependent RTK signaling. However, the role of FRS2 as an inhibitor of other EGFR family members remains unknown. FRS2 binds to phosphorylated and activated ERK. It possesses an ERK-binding site, and the binding between FRS2 and phosphorylated ERK is important for inhibition of the EGFR signaling. The ternary complex EGFR-FRS2-phosphorylated ERK may be required for the inhibition of EGFR signaling. This forms a negative feedback loop after the activation of ERKs downstream of the activated EGFR TK or to maintain the EGFR in an inactive state after the activation of ERKs by other stimuli. It is noteworthy that FRS2 expression does not appear to be induced by growth factors such as EGF. This characteristic distinguishes FRS2 from other negative feedback regulators.
2.3. SOCS3/SOCS4/SOCS5 SOCS proteins were originally identified as feedback inhibitors of cytokine signaling pathways. There are 8 members in the cytokine-inducible SH2-domain-containing protein (CIS)-SOCS family (CIS and SOCS1–SOCS7). Each of these proteins has a central SH2 domain and a C-terminal ∼40-amino acid domain that is known as a SOCS box (Yoshimura et al., 2007) (Fig. 1). The SOCS box interacts with elongin B and C, cullin-5, and RING box-2 (RBX-2) – one of the RING proteins – forming a large complex (Fig. 2C). SOCS proteins are called substrate receptors because the SH2 domain of a SOCS protein binds to a substrate for ubiquitinylation, while elongin B and C act as adaptors. The complex is called an E3 ubiquitin ligase complex in which the catalytic core is located in the RING domain to catalyze the transfer of ubiquitin from the active-site cysteine of an ubiquitin-conjugating enzyme (E2) to a lysine residue of a substrate. Recent evidences indicate that some members of the SOCS family act as feedback inhibitors of EGFR signaling. SOCS1 and SOCS3 bind not only to cytokine receptors but also to EGFRs. Among the family members, SOCS3, SOCS4, and SOCS5 are inducibly expressed in response to EGF (Kario et al., 2005). Subsequently, SOCS proteins bind to autophosphorylated EGFR via their SH2 domains and recruit the E3 ubiquitin ligase complex, leading to ubiquitinylation of EGFR; the ubiquitinylated EGFR acts as a substrate for degradation (Nicholson et al., 2005). It is important to note that SOCS5 does not appear to bind to the FGF or NGF receptor, indicating that its specific target is EGFR. The site at which EGFR binds to SOCS4 is a phosphorylated tyrosine residue at position 1092, known as the STAT3 site (Bullock et al., 2007). Thus, another mechanism for the attenuation of EGFR signaling may be that the attenuation occurs due to the competition between SOCS proteins and STAT3 for the same site.
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2.4. LRIG1 LRIG1 has recently been characterized as a negative feedback regulator of EGF signaling (Hedman and Henriksson, 2007). The human LRIG family comprises 3 members: LRIG1, LRIG2, and LRIG3. These are transmembrane proteins with an extracellular domain containing a leucine-rich repeat (LRR) and immunoglobulin-like domains, followed by a transmembrane region and further by a cytoplasmic tail (Fig. 1). LRIG1 mRNA expression is induced by certain growth factors such as EGF and androgen so that it functions as an immediate early-response gene. LRIG1 binds to all EGFR family members via its extracellular domain (Fig. 2D). Upregulation of LRIG1 expression is followed by enhanced ubiquitinylation and degradation of EGFR (Gur et al., 2004), the mechanism of which involves the recruitment of Cbl via the cytoplasmic juxtamembrane domain of LRIG1. Thereafter, the tyrosine-phosphorylated Cbl by activated TKs simultaneously ubiquitinylates EGFR and LRIG1 and then segregates them for degradation. The functions of LRIG2 and LRIG3 and the possibility of LRIG1 influencing the signaling of growth factor receptors other than the EGFR family members remain unclear. 2.4.1. Associated pathologies, therapeutic implications, and future prospects Mig-6/RALT-knockout mice exhibit hyperactivation of endogenous EGFRs and sustained signaling via the ERK pathway, resulting in the hyperproliferation and impaired differentiation of epidermal keratinocytes (Ferby et al., 2006). The mutant mice develop spontaneous tumors in various organs and are highly susceptible to chemically induced cutaneous tumorigenesis. Furthermore, the Mig-6/RALT transcript and protein levels are observed to be selectively and greatly decreased in ErbB2-amplified human breast cancer cell lines. This suggests that a downregulated Mig-6/RALT expression relieves the cells from the constraint on ErbB2-oncogenic signaling. All these findings indicate that Mig-6/RALT is a specific negative regulator of EGFR signaling in skin morphogenesis and a tumor suppressor in EGFR familydependent carcinogenesis. Occurrence of missense and nonsense mutations in the Mig-6/RALT coding region as well as transcriptional silencing in human lung cancer cells further emphasizes the role of Mig-6/RALT as a tumor suppressor gene (Zhang et al., 2007b). The FRS2 expression levels are lower in several cell lines derived from lung or breast cancer as compared with those in cells derived from corresponding normal tissues; this suggests that FRS2 exerts an inhibitory effect on tumorigenesis (Huang et al., 2006). No report on FRS2-knockout mice is available thus far. Further, the pathological roles of FRS2 largely remain to be elucidated. SOCS5-knockout mice show no overt phenotype in terms of lymphocyte function; however, whether SOCS5-knockout mice have any defects in EGF signaling remains unclear (Brender et al., 2004). LRIG1-knockout mice develop psoriatic lesions as a consequence of the hyperproliferation of epidermal keratinocytes (Hedman and Henriksson, 2007). Since psoriasis is associated with deregulated EGFR signaling, cell proliferation of normal skin could be coordinately regulated by EGFR and LRIG1. LRIG1 expression is downregulated in a variety of human cancer or tumor tissues (Hedman and Henriksson, 2007). Moreover, the EGFR/LRIG1 mRNA ratio is higher in kidney tumors than in the cortex of a normal kidney. LRIG1 expression is also downregulated in high-grade skin tumors and cervical carcinoma. These findings support the hypothesis that decreased expression of LRIG1 unleashes EGFR signaling, which might contribute to tumorigenesis. Thus, LRIG1 may act as a tumor suppressor. In contrast, LRIG1 expression remains unchanged or is even upregulated in several tumors, including
prostate cancer and leukemia. This poses a paradox that LRIG1 might be oncogenic in some cellular contexts. Recently, a considerable number of small compounds that inhibit EGFR family TKs and humanized antibodies against them have been developed; these function as targeting drugs and are currently used in the treatment of cancer patients. All the feedback inhibitors described in this review might be used as biomarkers that predict the efficacy of such targeting drugs. Since the EGFR family members contribute to cancer malignancy, they might also be used to predict the prognosis of cancer patients. Moreover, small compounds or peptides that stimulate these inhibitors would possibly serve as novel targeting drugs. Although the physiological and pathological functions of these inhibitors and the molecular mechanisms underlying their functioning remain to be validated and further elucidated, all such efforts should be useful in establishing personalized treatments in the near future. Acknowledgements This laboratory work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labor and Welfare of Japan for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; Ministry of Health, Labor and Welfare of Japan for Cancer research; Naito Foundation; and Cell Science Research Foundation. References Anastasi S, Fiorentino L, Fiorini M, Fraioli R, Sala G, Castellani L, et al. Feedback inhibition by RALT controls signal output by the ErbB network. Oncogene 2003;22:4221–34. Brender C, Columbus R, Metcalf D, Handman E, Starr R, Huntington N, et al. SOCS5 is expressed in primary B and T lymphoid cells but is dispensable for lymphocyte production and function. Mol Cell Biol 2004;24:6094–103. Bullock AN, Rodriguez MC, Debreczeni JE, Songyang Z, Knapp S. Structure of the SOCS4-ElonginB/C complex reveals a distinct SOCS box interface and the molecular basis for SOCS-dependent EGFR degradation. Structure 2007;15:1493–504. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006;7:505–16. Dikic I, Giordano S. Negative receptor signalling. Curr Opin Cell Biol 2003;15:128–35. Dixon SJ, MacDonald JI, Robinson KN, Kubu CJ, Meakin SO. Trk receptor binding and neurotrophin/fibroblast growth factor (FGF)-dependent activation of the FGF receptor substrate (FRS)-3. Biochim Biophys Acta 2006;1763:366–80. Ferby I, Reschke M, Kudlacek O, Knyazev P, Pante G, Amann K, et al. Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. Nat Med 2006;12:568–73. Fiorentino L, Pertica C, Fiorini M, Talora C, Crescenzi M, Castellani L, et al. Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain. Mol Cell Biol 2000;20:7735–50. Gotoh N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci 2008;99:1319–25. Gotoh N, Ito M, Yamamoto S, Yoshino I, Song N, Wang Y, et al. Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina. Proc Natl Acad Sci USA 2004a;101:17144–9 [Epub 2004 Nov 29]. Gotoh N, Laks S, Nakashima M, Lax I, Schlessinger J. FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial-temporal patterns of expression of their transcripts. FEBS Lett 2004b;564:14–8. Gotoh N, Manova K, Tanaka S, Murohashi M, Hadari Y, Lee A, et al. The docking protein FRS2alpha is an essential component of multiple fibroblast growth factor responses during early mouse development. Mol Cell Biol 2005;25:4105–16. Gur G, Rubin C, Katz M, Amit I, Citri A, Nilsson J, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J 2004;23:3270–81. Hedman H, Henriksson R. LRIG inhibitors of growth factor signaling—double-edged swords in human cancer? Eur J Cancer 2007;43:676–82. Huang L, Watanabe M, Chikamori M, Kido Y, Yamamoto T, Shibuya M, et al. Unique role of SNT-2/FRS2beta/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways. Oncogene 2006;25:6457–66. Kario E, Marmor MD, Adamsky K, Citri A, Amit I, Amariglio N, et al. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem 2005;280:7038–48. Kirisits A, Pils D, Krainer M. Epidermal growth factor receptor degradation: an alternative view of oncogenic pathways. Int J Biochem Cell Biol 2007;39:2173–82.
N. Gotoh / The International Journal of Biochemistry & Cell Biology 41 (2009) 511–515 Makkinje A, Quinn DA, Chen A, Cadilla CL, Force T, Bonventre JV, et al. Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress. J Biol Chem 2000;275:17838– 47. Nicholson SE, Metcalf D, Sprigg NS, Columbus R, Walker F, Silva A, et al. Suppressor of cytokine signaling (SOCS)-5 is a potential negative regulator of epidermal growth factor signaling. Proc Natl Acad Sci USA 2005;102:2328– 33. Pante G, Thompson J, Lamballe F, Iwata T, Ferby I, Barr FA, et al. Mitogen-inducible gene 6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth. J Cell Biol 2005;171:337–48. Sweeney C, Carraway 3rd KL. Negative regulation of ErbB family receptor tyrosine kinases. Br J Cancer 2004;90:289–93.
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Tsunoda T, Inokuchi J, Baba I, Okumura K, Naito S, Sasazuki T, et al. A novel mechanism of nuclear factor kappaB activation through the binding between inhibitor of nuclear factor-kappaBalpha and the processed NH(2)-terminal region of Mig-6. Cancer Res 2002;62:5668–71. Yamamoto S, Yoshino I, Shimazaki T, Murohashi M, Hevner RF, Lax I, et al. Essential role of Shp2-binding sites on FRS2alpha for corticogenesis and for FGF2dependent proliferation of neural progenitor cells. Proc Natl Acad Sci USA 2005;102:15983–8. Yoshimura A, Naka T, Kubo M. SOCS proteins, cytokine signalling and immune regulation. Nat Rev Immunol 2007;7:454–65. Zhang X, Pickin KA, Bose R, Jura N, Cole PA, Kuriyan J. Inhibition of the EGF receptor by binding of MIG6 to an activating kinase domain interface. Nature 2007a;450:741–4. Zhang YW, Staal B, Su Y, Swiatek P, Zhao P, Cao B, et al. Evidence that MIG-6 is a tumor-suppressor gene. Oncogene 2007b;26:269–76.
Contents lists available at ScienceDirect
The International Journal of Biochemistry & Cell Biology journal homepage: www.elsevier.com/locate/biocel
Signaling network in focus
Feedback inhibitors of the epidermal growth factor receptor signaling pathways Noriko Gotoh ∗ Division of Systems Biomedical Technology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, Japan
a r t i c l e
i n f o
Article history: Received 11 April 2008 Received in revised form 26 June 2008 Accepted 30 June 2008 Available online 9 August 2008 Keywords: Mig-6 RALT Gene 33 FRS2 SNT-2 FRS3 SOCS LRIG Ubiquitinylation Biomarker Cancer EGF ErbB HER
a b s t r a c t The epidermal growth factor receptor family tyrosine kinases transduce signals for cell proliferation and migration and contribute to tumorigenesis. A recent extensive research has highlighted the major roles of the negative regulators of complex epidermal growth factor receptor signaling networks. These regulators fine-tune signaling under physiological conditions. When their expression is downregulated, the resultant aberrant epidermal growth factor receptor signaling may promote cell proliferation and migration, leading to increased tumorigenesis. In this paper, I review specific feedback inhibitors that target epidermal growth factor receptors preferentially, via multiple modes of action. The inhibitors include mitogen-inducible gene-6 (Mig-6)/receptor-associated late transducer (RALT)/Gene 33, fibroblast growth factor receptor substrate 2 (FRS2)/suc1-associated neurotrophic factor target-2 (SNT-2)/FRS3, suppressor of cytokine signaling 3 (SOCS3)/SOCS4/SOCS5, and leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1). Although only fragmentary evidence is available regarding these inhibitors, they might be useful as cancer biomarkers, and the development of drugs that target them would certainly advance personalized medicine in the near future. © 2008 Elsevier Ltd. All rights reserved.
1. Introduction Signal transduction pathways via receptor tyrosine kinases (RTKs) play pivotal roles in numerous aspects of physiological and pathological biology. The epidermal growth factor receptor (EGFR) family, in particular, has been studied extensively as a prototype of RTKs since the 1980s (Citri and Yarden, 2006). It comprises the following 4 members: EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. These receptors homo- and heterodimerize, activating considerably complex signaling networks, and ultimately induce strong signals for cell proliferation and migration. There is sufficient evidence regarding the involvement of the abovementioned receptors in various cancer malignancies. The EGFR family members and their ligands are overexpressed in many types of cancers. Although less frequently, structural mutations occur in their ligand-binding domains, consequent to which these receptors constitutively dimerize and get activated. In contrast to the
∗ Tel.: +81 3 5449 5629; fax: +81 3 5449 5425. E-mail address: [email protected]. 1357-2725/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.biocel.2008.06.019
aberrant EGFR signaling under disease conditions such as cancer, signaling networks should be coordinated in a fine-tuned manner under physiological conditions. In the past decade, understanding of the direct participation of negative regulators in RTK signaling networks has enhanced considerably (Sweeney and Carraway, 2004). Emerging evidences indicate that there exist many negative regulators and that these regulators actually play major roles in regulating signaling networks via multiple modes of action. The coordinated actions of both positive and negative regulators qualitatively and quantitatively fine-tune signaling under physiological conditions. Further, it has been recognized that a loss of or decrease in the expression of negative regulators is related to cancer malignancy. There are certain general negative regulators/inhibitors of RTK signaling pathways. For example, Cbl – an E3 ubiquitin ligase – induces ubiquitinylation and degradation of signaling molecules that are activated by a variety of stimuli (Dikic and Giordano, 2003; Kirisits et al., 2007). In this review, I summarize the currently available information regarding the relatively specific negative regulators/inhibitors that preferentially target the EGFR family members.
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N. Gotoh / The International Journal of Biochemistry & Cell Biology 41 (2009) 511–515
Signaling network facts • Mitogen-inducible gene 6 (Mig-6)/receptor-associated late transducer (RALT)/Gene 33 is an early-response gene induced by epidermal growth factor (EGF). Mig-6/RALT acts as a negative feedback regulator of EGF receptor (EGFR). Its transcription is induced by the extracellular signal-regulated kinase (ERK) pathway that is activated by growth factors such as EGF or by multiple stimuli, including osmotic and mechanical stress. Mig-6/RALT/Gene 33 binds to the tyrosine kinase (TK) domains of EGFR and ErbB2 and inhibits the TK activity. • Fibroblast growth factor receptor substrate 2 beta (FRS2), also termed suc1-associated neurotrophic factor target-2 (SNT-2) and FRS3, constitutively binds to EGFR, regardless of ligand stimulation. After activation of ERK by various growth factors, including EGF, the phosphorylated ERK binds to FRS2 and inhibits EGFR autophosphorylation and signal transduction. Thus, FRS2 acts as a negative feedback regulator of EGFR. • Suppressor of cytokine signaling 3 (SOCS3)/SOCS4/SOCS5 is an early-response gene induced by EGF. SOCS proteins are negative feedback regulators of EGFR. They bind to autophosphorylated EGFR via their Src homology 2 (SH2) domains and recruit E3 ubiquitin ligase complex via their SOCS domains, leading to the ubiquitinylation and degradation of EGFR. • Leucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is an early-response gene induced by EGF. LRIG1 acts as a negative feedback regulator of EGFR. It binds to EGFR via its extracellular domain and recruits Cbl – an E3 ubiquitin ligase – via its cytoplasmic domain, leading to the ubiquitinylation and degradation of EGFR.
2. Key molecules, cascades, and functions 2.1. Mig-6/RALT/Gene 33 Mig-6/RALT is a multiadaptor protein that has many interactive domains (Fig. 1). Mig-6 was originally identified as an immediate early-response gene induced by stimulation with fetal calf serum, insulin, and growth factors, including EGF. Transcription of Mig-6 is induced by an array of extracellular stimuli, including osmotic stress and mechanical stress (Makkinje et al., 2000). On the other hand, yeast two-hybrid screening performed using ErbB2 containing the TK domain as bait also identified Mig-6 that was renamed RALT (Fiorentino et al., 2000). Mig-6/RALT binds to all EGFR family members via its ErbB2binding domain and inhibits the TK activity (Anastasi et al., 2003) (Fig. 2A). The binding between Mig-6/RALT and the EGFR family TKs occurs only after ligand activation. Since the ErbB2-binding domain specifically interacts with the TK domain of EGFR and ErbB2, Mig6/RALT acts as a specific inhibitor of signaling via the EGFR family TKs. Signals for the induction of Mig-6/RALT expression by various stimuli are transduced via the Ras/ERK pathway. Since the EGFR family TKs strongly activate this pathway, Mig-6/RALT serves as a feedback inhibitor. Recently, the crystal structure of a complex between the EGFR TK domain and a fragment of the ErbB2-binding domain of Mig6/RALT was resolved (Zhang et al., 2007a). Before activation, the EGFR TK domain has an autoinhibited conformation that resembles that of inactive cyclin-dependent kinases (CDKs). Conversion to the active form requires interactions between the distal surface of the carboxy-terminal lobe (C lobe) of 1 kinase domain and the amino-terminal lobe of the other kinase domain in the asym-
metric activating dimer. The amino-terminal of the ErbB2-binding domain fragment of Mig-6/RALT binds to the distal surface of the C lobe of the EGFR TK domain. Therefore, Mig-6/RALT-mediated inhibition of the TK activity is due to the blockade of the dimer’s interface. Further, Mig-6/RALT is involved in signaling by other modes via its Cdc42/Rac interaction and binding (CRIB) domain. Mig-6/RALT binds to the GTP-bound form of Cdc42 via the CRIB domain and activates stress-activated protein kinase (SAPK) (Makkinje et al., 2000). It has been reported that the binding of Mig-6/RALT to Cdc42 inhibits the activity of Cdc42, resulting in the inhibition of hepatocyte growth factor (HGF)-induced cell migration (Pante et al., 2005). It is also reported that limited proteolytic processing yields the NH2 -terminal fragment of Mig-6/RALT containing the CRIB domain. The processed CRIB domain of Mig-6/RALT binds to inhibitory B␣ (IB␣) and competes with nuclear factor B (NFB), which is a binding partner of IB␣ in the inactive state, resulting in the activation of NFB (Tsunoda et al., 2002). 2.2. FRS2ˇ FRS2, also termed SNT-2 or FRS3, belongs to the FRS2 family of docking/scaffold adaptor proteins. This family comprises 2 members, FRS2␣ and FRS2, in mammals (Gotoh, 2008). Both members contain N-terminal myristylation sites for distribution on plasma membrane and a phosphotyrosine-binding (PTB) domain for binding to a limited number of RTK species, including fibroblast growth factor (FGF) receptor and nerve growth factor (NGF) receptor (Fig. 1). The activation of these RTKs enables phosphorylation of FRS2 at tyrosine residues and its subsequent binding to Grb2 and Shp2, an SH2 domain-containing adaptor protein and a tyrosine phosphatase, respectively. Subsequently, Shp2 activates the Ras/ERK pathway and Grb2 activates the Ras/ERK, phosphatidylinositol (PI) 3-kinase, and ubiquitinylation/degradation pathways by binding to Son of sevenless (SOS), Grb2-associated binder 1 (Gab1) and Cbl, respectively, via the Src homology 3 (SH3) domains of Grb2. FRS2␣ acts as “a conning center” in FGF signaling. In fact, genetically engineered FRS2␣ mutant mice exhibit a variety of phe-
Fig. 1. Schematic structures of the inhibitors of the epidermal growth factor receptor (EGFR) family members. In Mig-6/RALT, the proline-rich sequence binds to the Src homology 3 (SH3) domain of Grb2, the 14–3-3 binding domain (BD) binds to 14–33, and the ErbB2-binding domain (EBD) binds to the ErbB2 tyrosine kinase (TK) domain. The AH domain (AHD) is homologous to the Ack TK. The PTB domain of FRS2 binds to a phosphorylated tyrosine (Y) residue of the NGF receptor or the unphosphorylated juxtamembrane region of the FGF receptor. SP, signal peptide; LRR, leucine-rich repeats; Ig, immunoglobulin-like domain; TM, transmembrane domain.
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Fig. 2. Multiple modes of action of the inhibitors. (A) Mig-6/RALT transcription is induced by the activation of ERK pathway via activated EGFR or other stimuli. The translated Mig-6/RALT binds to the activated TK domain of EGFR and ErbB2 and inhibits the TK activity. (B) FRS2 constitutively binds to EGFR. Activated EGFR or other stimuli activate the ERK pathway. The activated ERK binds to FRS2 and inhibits the EGFR signaling. (C) SOCS3, SOCS4, or SOCS5 transcription is induced by stimulation with EGF. The translated SOCS3/SOCS4/SOCS5 binds to the autophosphorylated EGFR via its SH2 domain and recruits the E3 ubiquitin ligase complex via its SOCS box. (D) LRIG1 transcription is induced by stimulation with EGF. The translated LRIG1 binds to EGFR family members via its extracellular domain and recruits Cbl E3 ubiquitin ligase to its cytoplasmic tail, inducing ubiquitinylation/degradation of the EGFR family members.
notypes due to defects in FGF signaling in vivo (Gotoh et al., 2004a, 2005; Yamamoto et al., 2005). In contrast to the well-known functions of FRS2␣, the functions of FRS2 have long been unclear. FRS2 compensates for the loss of FRS2␣ and activates ERK in Frs2˛−/− mouse embryonic fibroblasts (MEFs) in response to FGF (Gotoh et al., 2004b). However, FRS2␣, but not FRS2, potentiates neurite outgrowth in PC12 cells in response to NGF, indicating that FRS2␣ and FRS2 are not completely redundant (Dixon et al., 2006). It has recently been unraveled that FRS2 plays a novel role of inhibiting EGF signaling. This was evident from the finding that FRS2 expression inhibits EGF-induced cell proliferation and transformation (Huang et al., 2006). The PTB domain of FRS2 constitutively binds to EGFRs, regardless of the absence or presence of ligands; however, FRS2 does not get phosphorylated at tyrosine residues by EGFR TK. Instead, it inhibits EGFR autophosphorylation, resulting in the inhibition of its downstream signaling (Fig. 2B). In contrast, FRS2␣ is phosphorylated at tyrosine residues by EGFR TK in cells where EGFRs are overexpressed. Therefore, FRS2 is a unique scaffolding adaptor that serves both as a negative and a positive regulator for receptor species-dependent RTK signaling. However, the role of FRS2 as an inhibitor of other EGFR family members remains unknown. FRS2 binds to phosphorylated and activated ERK. It possesses an ERK-binding site, and the binding between FRS2 and phosphorylated ERK is important for inhibition of the EGFR signaling. The ternary complex EGFR-FRS2-phosphorylated ERK may be required for the inhibition of EGFR signaling. This forms a negative feedback loop after the activation of ERKs downstream of the activated EGFR TK or to maintain the EGFR in an inactive state after the activation of ERKs by other stimuli. It is noteworthy that FRS2 expression does not appear to be induced by growth factors such as EGF. This characteristic distinguishes FRS2 from other negative feedback regulators.
2.3. SOCS3/SOCS4/SOCS5 SOCS proteins were originally identified as feedback inhibitors of cytokine signaling pathways. There are 8 members in the cytokine-inducible SH2-domain-containing protein (CIS)-SOCS family (CIS and SOCS1–SOCS7). Each of these proteins has a central SH2 domain and a C-terminal ∼40-amino acid domain that is known as a SOCS box (Yoshimura et al., 2007) (Fig. 1). The SOCS box interacts with elongin B and C, cullin-5, and RING box-2 (RBX-2) – one of the RING proteins – forming a large complex (Fig. 2C). SOCS proteins are called substrate receptors because the SH2 domain of a SOCS protein binds to a substrate for ubiquitinylation, while elongin B and C act as adaptors. The complex is called an E3 ubiquitin ligase complex in which the catalytic core is located in the RING domain to catalyze the transfer of ubiquitin from the active-site cysteine of an ubiquitin-conjugating enzyme (E2) to a lysine residue of a substrate. Recent evidences indicate that some members of the SOCS family act as feedback inhibitors of EGFR signaling. SOCS1 and SOCS3 bind not only to cytokine receptors but also to EGFRs. Among the family members, SOCS3, SOCS4, and SOCS5 are inducibly expressed in response to EGF (Kario et al., 2005). Subsequently, SOCS proteins bind to autophosphorylated EGFR via their SH2 domains and recruit the E3 ubiquitin ligase complex, leading to ubiquitinylation of EGFR; the ubiquitinylated EGFR acts as a substrate for degradation (Nicholson et al., 2005). It is important to note that SOCS5 does not appear to bind to the FGF or NGF receptor, indicating that its specific target is EGFR. The site at which EGFR binds to SOCS4 is a phosphorylated tyrosine residue at position 1092, known as the STAT3 site (Bullock et al., 2007). Thus, another mechanism for the attenuation of EGFR signaling may be that the attenuation occurs due to the competition between SOCS proteins and STAT3 for the same site.
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2.4. LRIG1 LRIG1 has recently been characterized as a negative feedback regulator of EGF signaling (Hedman and Henriksson, 2007). The human LRIG family comprises 3 members: LRIG1, LRIG2, and LRIG3. These are transmembrane proteins with an extracellular domain containing a leucine-rich repeat (LRR) and immunoglobulin-like domains, followed by a transmembrane region and further by a cytoplasmic tail (Fig. 1). LRIG1 mRNA expression is induced by certain growth factors such as EGF and androgen so that it functions as an immediate early-response gene. LRIG1 binds to all EGFR family members via its extracellular domain (Fig. 2D). Upregulation of LRIG1 expression is followed by enhanced ubiquitinylation and degradation of EGFR (Gur et al., 2004), the mechanism of which involves the recruitment of Cbl via the cytoplasmic juxtamembrane domain of LRIG1. Thereafter, the tyrosine-phosphorylated Cbl by activated TKs simultaneously ubiquitinylates EGFR and LRIG1 and then segregates them for degradation. The functions of LRIG2 and LRIG3 and the possibility of LRIG1 influencing the signaling of growth factor receptors other than the EGFR family members remain unclear. 2.4.1. Associated pathologies, therapeutic implications, and future prospects Mig-6/RALT-knockout mice exhibit hyperactivation of endogenous EGFRs and sustained signaling via the ERK pathway, resulting in the hyperproliferation and impaired differentiation of epidermal keratinocytes (Ferby et al., 2006). The mutant mice develop spontaneous tumors in various organs and are highly susceptible to chemically induced cutaneous tumorigenesis. Furthermore, the Mig-6/RALT transcript and protein levels are observed to be selectively and greatly decreased in ErbB2-amplified human breast cancer cell lines. This suggests that a downregulated Mig-6/RALT expression relieves the cells from the constraint on ErbB2-oncogenic signaling. All these findings indicate that Mig-6/RALT is a specific negative regulator of EGFR signaling in skin morphogenesis and a tumor suppressor in EGFR familydependent carcinogenesis. Occurrence of missense and nonsense mutations in the Mig-6/RALT coding region as well as transcriptional silencing in human lung cancer cells further emphasizes the role of Mig-6/RALT as a tumor suppressor gene (Zhang et al., 2007b). The FRS2 expression levels are lower in several cell lines derived from lung or breast cancer as compared with those in cells derived from corresponding normal tissues; this suggests that FRS2 exerts an inhibitory effect on tumorigenesis (Huang et al., 2006). No report on FRS2-knockout mice is available thus far. Further, the pathological roles of FRS2 largely remain to be elucidated. SOCS5-knockout mice show no overt phenotype in terms of lymphocyte function; however, whether SOCS5-knockout mice have any defects in EGF signaling remains unclear (Brender et al., 2004). LRIG1-knockout mice develop psoriatic lesions as a consequence of the hyperproliferation of epidermal keratinocytes (Hedman and Henriksson, 2007). Since psoriasis is associated with deregulated EGFR signaling, cell proliferation of normal skin could be coordinately regulated by EGFR and LRIG1. LRIG1 expression is downregulated in a variety of human cancer or tumor tissues (Hedman and Henriksson, 2007). Moreover, the EGFR/LRIG1 mRNA ratio is higher in kidney tumors than in the cortex of a normal kidney. LRIG1 expression is also downregulated in high-grade skin tumors and cervical carcinoma. These findings support the hypothesis that decreased expression of LRIG1 unleashes EGFR signaling, which might contribute to tumorigenesis. Thus, LRIG1 may act as a tumor suppressor. In contrast, LRIG1 expression remains unchanged or is even upregulated in several tumors, including
prostate cancer and leukemia. This poses a paradox that LRIG1 might be oncogenic in some cellular contexts. Recently, a considerable number of small compounds that inhibit EGFR family TKs and humanized antibodies against them have been developed; these function as targeting drugs and are currently used in the treatment of cancer patients. All the feedback inhibitors described in this review might be used as biomarkers that predict the efficacy of such targeting drugs. Since the EGFR family members contribute to cancer malignancy, they might also be used to predict the prognosis of cancer patients. Moreover, small compounds or peptides that stimulate these inhibitors would possibly serve as novel targeting drugs. Although the physiological and pathological functions of these inhibitors and the molecular mechanisms underlying their functioning remain to be validated and further elucidated, all such efforts should be useful in establishing personalized treatments in the near future. Acknowledgements This laboratory work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; Ministry of Health, Labor and Welfare of Japan for the 3rd-term Comprehensive 10-year Strategy for Cancer Control; Ministry of Health, Labor and Welfare of Japan for Cancer research; Naito Foundation; and Cell Science Research Foundation. References Anastasi S, Fiorentino L, Fiorini M, Fraioli R, Sala G, Castellani L, et al. Feedback inhibition by RALT controls signal output by the ErbB network. Oncogene 2003;22:4221–34. Brender C, Columbus R, Metcalf D, Handman E, Starr R, Huntington N, et al. SOCS5 is expressed in primary B and T lymphoid cells but is dispensable for lymphocyte production and function. Mol Cell Biol 2004;24:6094–103. Bullock AN, Rodriguez MC, Debreczeni JE, Songyang Z, Knapp S. Structure of the SOCS4-ElonginB/C complex reveals a distinct SOCS box interface and the molecular basis for SOCS-dependent EGFR degradation. Structure 2007;15:1493–504. Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 2006;7:505–16. Dikic I, Giordano S. Negative receptor signalling. Curr Opin Cell Biol 2003;15:128–35. Dixon SJ, MacDonald JI, Robinson KN, Kubu CJ, Meakin SO. Trk receptor binding and neurotrophin/fibroblast growth factor (FGF)-dependent activation of the FGF receptor substrate (FRS)-3. Biochim Biophys Acta 2006;1763:366–80. Ferby I, Reschke M, Kudlacek O, Knyazev P, Pante G, Amann K, et al. Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation. Nat Med 2006;12:568–73. Fiorentino L, Pertica C, Fiorini M, Talora C, Crescenzi M, Castellani L, et al. Inhibition of ErbB-2 mitogenic and transforming activity by RALT, a mitogen-induced signal transducer which binds to the ErbB-2 kinase domain. Mol Cell Biol 2000;20:7735–50. Gotoh N. Regulation of growth factor signaling by FRS2 family docking/scaffold adaptor proteins. Cancer Sci 2008;99:1319–25. Gotoh N, Ito M, Yamamoto S, Yoshino I, Song N, Wang Y, et al. Tyrosine phosphorylation sites on FRS2alpha responsible for Shp2 recruitment are critical for induction of lens and retina. Proc Natl Acad Sci USA 2004a;101:17144–9 [Epub 2004 Nov 29]. Gotoh N, Laks S, Nakashima M, Lax I, Schlessinger J. FRS2 family docking proteins with overlapping roles in activation of MAP kinase have distinct spatial-temporal patterns of expression of their transcripts. FEBS Lett 2004b;564:14–8. Gotoh N, Manova K, Tanaka S, Murohashi M, Hadari Y, Lee A, et al. The docking protein FRS2alpha is an essential component of multiple fibroblast growth factor responses during early mouse development. Mol Cell Biol 2005;25:4105–16. Gur G, Rubin C, Katz M, Amit I, Citri A, Nilsson J, et al. LRIG1 restricts growth factor signaling by enhancing receptor ubiquitylation and degradation. EMBO J 2004;23:3270–81. Hedman H, Henriksson R. LRIG inhibitors of growth factor signaling—double-edged swords in human cancer? Eur J Cancer 2007;43:676–82. Huang L, Watanabe M, Chikamori M, Kido Y, Yamamoto T, Shibuya M, et al. Unique role of SNT-2/FRS2beta/FRS3 docking/adaptor protein for negative regulation in EGF receptor tyrosine kinase signaling pathways. Oncogene 2006;25:6457–66. Kario E, Marmor MD, Adamsky K, Citri A, Amit I, Amariglio N, et al. Suppressors of cytokine signaling 4 and 5 regulate epidermal growth factor receptor signaling. J Biol Chem 2005;280:7038–48. Kirisits A, Pils D, Krainer M. Epidermal growth factor receptor degradation: an alternative view of oncogenic pathways. Int J Biochem Cell Biol 2007;39:2173–82.
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