Abstract
Previously, we demonstrated that SGEF enhances EGFR stability; however, SGEF-mediated downstream signaling of EGFR is not well understood. Here, we show that SGEF enhances EGF-induced ERK1/2 activation independent of its guanine nucleotide exchange (GEF) activity. We further show that SGEF interacts with Grb2, a critical downstream transducer of EGFR. Surprisingly, we found that interaction of Grb2 to SGEF antagonizes the ability of SGEF to enhance EGF-induced ERK1/2 activation. Taken together, this study reports a novel function of SGEF that excludes GEF and also provides important insights into the complex role of Grb2 in EGFR signal transduction.
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Abbreviations
- SGEF:
-
SH3-containing guanine nucleotide exchange factor
- EGFR:
-
Epidermal growth factor receptor
- EGF:
-
Epidermal growth factor
- GEF:
-
Guanine nucleotide exchange factor
- PTB:
-
Phosphotyrosine binding
- SH2:
-
Src homology 2
- SH3:
-
Src homology 3
- Pro:
-
Proline-rich domain
References
Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW, Burgess AW (2003) Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res 284:31–53
Herbst RS (2004) Review of epidermal growth factor receptor biology. Int J Radiat Oncol Biol Phys 59:21–26
Yarden Y, Sliwkowski MX (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2:127–137
Olayioye MA, Neve RM, Lane HA, Hynes NE (2000) The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J 19:3159–3167
Schlessinger J (2000) Cell signaling by receptor tyrosine kinases. Cell 103:211–225
Batzer AG, Rotin D, Urena JM, Skolnik EY, Schlessinger J (1994) Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor. Mol Cell Biol 14:5192–5201
Chardin P, Camonis JH, Gale NW, van Aelst L, Schlessinger J, Wigler MH, Bar-Sagi D (1993) Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science 260:1338–1343
Li N, Batzer A, Daly R, Yajnik V, Skolnik E, Chardin P, Bar-Sagi D, Margolis B, Schlessinger J (1993) Guanine-nucleotide-releasing factor hSos1 binds to Grb2 and links receptor tyrosine kinases to Ras signalling. Nature 363:85–88
Robinson MJ, Cobb MH (1997) Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9:180–186
Wang H, Li S, Li H, Li C, Guan K, Luo G, Yu L, Wu R, Zhang X, Wang J, Zhou J (2013) SGEF enhances EGFR stability through delayed EGFR trafficking from early to late endosomes. Carcinogenesis 34:1976–1983
Wang H, Wu R, Yu L, Wu F, Li S, Zhao Y, Li H, Luo G, Wang J, Zhou J (2012) SGEF is overexpressed in prostate cancer and contributes to prostate cancer progression. Oncol Rep 28:1468–1474
van Buul JD, Allingham MJ, Samson T, Meller J, Boulter E, Garcia-Mata R, Burridge K (2007) RhoG regulates endothelial apical cup assembly downstream from ICAM1 engagement and is involved in leukocyte trans-endothelial migration. J Cell Biol 178:1279–1293
Patel JC, Galan JE (2006) Differential activation and function of Rho GTPases during Salmonella-host cell interactions. J Cell Biol 175:453–463
Ellerbroek SM, Wennerberg K, Arthur WT, Dunty JM, Bowman DR, DeMali KA, Der C, Burridge K (2004) SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis. Mol Biol Cell 15:3309–3319
Krishna Subbaiah V, Massimi P, Boon SS, Myers MP, Sharek L, Garcia-Mata R, Banks L (2012) The invasive capacity of HPV transformed cells requires the hDlg-dependent enhancement of SGEF/RhoG activity. PLoS Pathog 8:e1002543
Yu H, Chen JK, Feng S, Dalgarno DC, Brauer AW, Schrelber SL (1994) Structural basis for the binding of proline-rich peptides to SH3 domains. Cell 76:933–945
Mebratu Y, Tesfaigzi Y (2009) How ERK1/2 activation controls cell proliferation and cell death: is subcellular localization the answer? Cell Cycle 8:1168–1175
Kao S, Jaiswal RK, Kolch W, Landreth GE (2001) Identification of the mechanisms regulating the differential activation of the mapk cascade by epidermal growth factor and nerve growth factor in PC12 cells. J Biol Chem 276:18169–18177
Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185
Wong ES, Fong CW, Lim J, Yusoff P, Low BC, Langdon WY, Guy GR (2002) Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling. EMBO J 21:4796–4808
Traverse S, Seedorf K, Paterson H, Marshall CJ, Cohen P, Ullrich A (1994) EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr Biol 4:694–701
Haglund K, Schmidt MH, Wong ES, Guy GR, Dikic I (2005) Sprouty2 acts at the Cbl/CIN85 interface to inhibit epidermal growth factor receptor downregulation. EMBO Rep 6:635–641
Ren Y, Cheng L, Rong Z, Li Z, Li Y, Zhang X, Xiong S, Hu J, Fu XY, Chang Z (2008) hSef potentiates EGF-mediated MAPK signaling through affecting EGFR trafficking and degradation. Cell Signal 20:518–533
Gan Y, Shi C, Inge L, Hibner M, Balducci J, Huang Y (2010) Differential roles of ERK and Akt pathways in regulation of EGFR-mediated signaling and motility in prostate cancer cells. Oncogene 29:4947–4958
Giubellino A, Burke TR Jr, Bottaro DP (2008) Grb2 signaling in cell motility and cancer. Expert Opin Ther Targets 12:1021–1033
Acknowledgments
We thank Dr. Wannian Yang for providing materials. This work was supported by the grants from the National Natural Science Foundation of China (No. 81372770 to J.Z. and Nos. 81172445 and 81372140 to J.W.).
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Wang, H., Li, S., Li, H. et al. Grb2 interacts with SGEF and antagonizes the ability of SGEF to enhance EGF-induced ERK1/2 activation. Mol Cell Biochem 389, 239–247 (2014). https://doi.org/10.1007/s11010-013-1945-7
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DOI: https://doi.org/10.1007/s11010-013-1945-7