Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

GRB10

  • Nuzhat N. Kabir
  • Lars Rönnstrand
  • Julhash U. Kazi
Reference work entry
First Online:
DOI: https://doi.org/10.1007/978-3-319-67199-4_101665
Download entry PDF
How to cite

Synonyms

 Grb-10;  GRB-IR;  IRBP;  MEG1;  RSS

Historical Background

The Src Homology 2 (SH2) domain-containing adaptor proteins are a class of signal transducers downstream of growth factor receptors. The human genome encodes more than one hundred SH2 domain-containing proteins. The GRB7 family of SH2 domain-containing adaptor proteins includes three members: GRB7, GRB10, and GRB14. All three family members have the same domain structure (Fig. 1). Human GRB10 was originally identified in a yeast-two hybrid screen using the insulin receptor (IR) as bait and named as GRB-IR (Liu and Roth 1995).
GRB10, Fig. 1

GRB7 family proteins share similar domains. GRB7 family proteins share a similar domain arrangement. An N-terminal still un-characterized region followed by a RAS-associated like (RA) domain, which is known to bind with RAS superfamily proteins. The pleckstrin homology (PH) domain binds to phospholipids and recruits proteins to the cell membrane. The Src Homology 2 (SH2) domain is a phosphotyrosine-binding domain. Between PH and SH2 domains (BPS) is a characteristic domain for GRB7 family proteins that is known to be essential for interaction with insulin receptors

The GRB10 Gene and Its Splice Variants

The human GRB10 gene encodes three alternative splice variants known as GRB10 alpha, GRB10 beta, and GRB10 gamma. The GRB10 gene is located to human chromosome 7p11.2-p12. GRB10 gamma is the longest expressed protein with all domains intact (Fig. 2). GRB10 alpha lacks a part of the PH domain, while GRB10 beta has a shorter N-terminal region. The N-terminal region of GRB10 has several proline-rich (PXXP) regions, which are possible binding sites for SRC Homology 3 (SH3) domains. GRB10 expression was described in various human tissues including brain, cardiac muscle, colon, kidney, liver, lung, ovary, pancreas, placenta, prostate, skeletal muscle, small intestine, spleen, and testis (Liu and Roth 1995; Hansen et al. 1996; Dong et al. 1997; Frantz et al. 1997).
GRB10, Fig. 2

GRB10 splice variants. GRB10 gene encodes three different alternative splice variants. GRB10 alpha has a shorter PH domain, but all other functional domains are same as in the other two variants. GRB10 beta lacks a short part of the N-terminal region

GRB10 Interacting Proteins

Human GRB10 has been reported to be associated with receptor tyrosine kinases, nonreceptor tyrosine kinases, and other signaling proteins (Kabir and Kazi 2014). All three human splice variants of GRB10 interact with the insulin receptor (InsR) and negatively regulate insulin signaling (Liu and Roth 1995; Ramos et al. 2006; Yu et al. 2011). The interaction is dependent on insulin stimulation and InsR-pY1322 residue recruits the GRB10-SH2 domain. The insulin-like growth factor 1 receptor (IGF-1R) is another target of GRB10 (Stein et al. 2001). Although GRB10 associates with insulin receptors, no associations were reported with insulin receptor substrates. GRB10 displays a comparatively higher preference for interaction with the InsR than with the IGF-1R (Laviola et al. 1997). The interaction between GRB10 and the insulin receptor is not only mediated through the GRB10-SH2 domain, but also GRB10-BPS domain is involved. InsR and IGF-1R display differential affinity for the SH2 and BPS domains of GRB10, thus explaining the difference in preference for interaction with InsR and IGF-1R (He et al. 1998). The type III receptor tyrosine kinase FLT3 associates with GRB10, and the association is mediated by two phosphotyrosine residues (pY572 and pY793) in FLT3 (Kazi and Rönnstrand 2013). Other GRB10 interacting proteins include the serine/threonine kinases mTORC1, MEK1, RAF1, and ERK1/2 and the tyrosine kinases KDR, TEC, ABL, EGFR, PDGFR, SRC, and FYN etc. (Kabir and Kazi 2014).

GRB10 in Receptor Tyrosine Kinase Signaling

GRB10 has been shown to regulate receptor tyrosine kinase signaling in different ways. Binding of GRB10 to the activated InsR has been shown to potentiate cell proliferation through Gab1 (Deng et al. 2008). Another report suggested that GRB10 has the ability of recruiting the p85 subunit of PI3K in response to insulin stimulation (Deng et al. 2003). Activation of PI3K leads to activation of survival signaling through AKT activation. Therefore, it is likely that GRB10 regulates multiple signaling cascades downstream of the InsR. Insulin stimulation in turn induces GRB10 tyrosine phosphorylation on Y67 which is mediated by SRC family nonreceptor tyrosine kinases (Langlais et al. 2000). Phosphorylation of Y67 by SRC reduces the binding affinity of GRB10 for the InsR, suggesting that a negative feedback loop is involved. However, further studies are required in order to define the exact role of GRB10-pY67 in insulin-mediated biological events. GRB10 displays a constitutive association with the E3 ubiquitin ligase NEDD4, which is mediated through the GRB10 SH2 and/or BPS domain (Morrione et al. 1999). NEDD4 did not induce GRB10 degradation but affected IGF-1R stability in response to the ligand, demonstrating that GRB10 links a ubiquitin ligase to the receptor and accelerates receptor degradation through ubiquitination (Vecchione et al. 2003). Thus, it is likely that GRB10 negatively regulates receptor signaling through ubiquitin-mediated degradation of the receptors. GRB10γ competes with InsR substrates IRS1 and IRS2 for binding, resulting in negative regulation of insulin-induced AKT phosphorylation (Wick et al. 2003). Another mechanism of negative regulation is mTORC1-mediated phosphorylation of GRB10 that leads to feedback inhibition of PI3K signaling (Hsu et al. 2011; Yu et al. 2011). Besides the insulin receptors, GRB10 expression in cultured cell lines potentiates ligand-induced mitogenic signaling downstream of several type III receptor tyrosine kinases, including PDGFR, KIT, and FLT3 (Wang et al. 1999; Jahn et al. 2002; Kazi and Rönnstrand 2013). Figure 3 describes how GRB10 mediates regulation of insulin receptor and type III receptor tyrosine kinase signaling.
GRB10, Fig. 3

GRB10 in InsR and FLT3 signaling. Upon binding the ligand, receptors dimerize and autophosphorylate on tyrosine residues. GRB10 associates with tyrosine phosphorylated receptors and recruits other signaling proteins, such as Gab1 or PI3K, leading to activation of proliferative signaling and survival signaling. GRB10 also can recruit ubiquitin ligase which direct receptors to ubiquitination-mediated degradation

Summary

GRB10 is an important component of receptor tyrosine kinase signaling. The presence of multiple domains facilitates interaction between GRB10 and different signaling proteins. GRB10 has been extensively studied with respect to insulin signaling. Current studies suggest that GRB10 is also an essential component of the signaling machinery of other receptor tyrosine kinases. Current studies suggest that depending on the cell type, splice variant, and interaction partners, GRB10 differentially regulates receptor downstream signaling. GRB10 enhances receptor signaling through recruitment of signaling proteins such as GAB1 or PI3K. On the other hand, by recruiting E3 ubiquitin ligases such as NEDD4 or competing with the substrate proteins, for example, IRS1 and IRS2, GRB10 negatively regulates receptor signaling.

References

  1. Deng Y, Bhattacharya S, Swamy OR, Tandon R, Wang Y, Janda R, et al. Growth factor receptor-binding protein 10 (Grb10) as a partner of phosphatidylinositol 3-kinase in metabolic insulin action. J Biol Chem. 2003;278:39311–22. doi: 10.1074/jbc.M304599200.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Deng Y, Zhang M, Riedel H. Mitogenic roles of Gab1 and Grb10 as direct cellular partners in the regulation of MAP kinase signaling. J Cell Biochem. 2008;105:1172–82. doi: 10.1002/jcb.21829.PubMedCrossRefPubMedCentralGoogle Scholar
  3. Dong LQ, Du H, Porter SG, Kolakowski Jr LF, Lee AV, Mandarino LJ, et al. Cloning, chromosome localization, expression, and characterization of an Src homology 2 and pleckstrin homology domain-containing insulin receptor binding protein hGrb10gamma. J Biol Chem. 1997;272:29104–12.PubMedCrossRefGoogle Scholar
  4. Frantz JD, Giorgetti-Peraldi S, Ottinger EA, Shoelson SE. Human GRB-IRbeta/GRB10. Splice variants of an insulin and growth factor receptor-binding protein with PH and SH2 domains. J Biol Chem. 1997;272:2659–67.PubMedCrossRefGoogle Scholar
  5. Hansen H, Svensson U, Zhu J, Laviola L, Giorgino F, Wolf G, et al. Interaction between the Grb10 SH2 domain and the insulin receptor carboxyl terminus. J Biol Chem. 1996;271:8882–6.PubMedCrossRefGoogle Scholar
  6. He W, Rose DW, Olefsky JM, Gustafson TA. Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains. J Biol Chem. 1998;273:6860–7.PubMedCrossRefGoogle Scholar
  7. Hsu PP, Kang SA, Rameseder J, Zhang Y, Ottina KA, Lim D, et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling. Science. 2011;332:1317–22. doi: 10.1126/science.1199498.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Jahn T, Seipel P, Urschel S, Peschel C, Duyster J. Role for the adaptor protein Grb10 in the activation of Akt. Mol Cell Biol. 2002;22:979–91.PubMedCrossRefPubMedCentralGoogle Scholar
  9. Kabir NN, Kazi JU. Grb10 is a dual regulator of receptor tyrosine kinase signaling. Mol Biol Rep. 2014;41:1985–92. doi: 10.1007/s11033-014-3046-4.PubMedCrossRefPubMedCentralGoogle Scholar
  10. Kazi JU, Rönnstrand L. FLT3 signals via the adapter protein Grb10 and overexpression of Grb10 leads to aberrant cell proliferation in acute myeloid leukemia. Mol Oncol. 2013;7:402–18. doi: 10.1016/j.molonc.2012.11.003.PubMedCrossRefPubMedCentralGoogle Scholar
  11. Langlais P, Dong LQ, Hu D, Liu F. Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family. Oncogene. 2000;19:2895–903. doi: 10.1038/sj.onc.1203616.PubMedCrossRefPubMedCentralGoogle Scholar
  12. Laviola L, Giorgino F, Chow JC, Baquero JA, Hansen H, Ooi J, et al. The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts. J Clin Invest. 1997;99:830–7. doi: 10.1172/JCI119246.PubMedCrossRefPubMedCentralGoogle Scholar
  13. Liu F, Roth RA. Grb-IR: a SH2-domain-containing protein that binds to the insulin receptor and inhibits its function. Proc Natl Acad Sci USA. 1995;92:10287–91.PubMedCrossRefPubMedCentralGoogle Scholar
  14. Morrione A, Plant P, Valentinis B, Staub O, Kumar S, Rotin D, et al. mGrb10 interacts with Nedd4. J Biol Chem. 1999;274:24094–9.PubMedCrossRefGoogle Scholar
  15. Ramos FJ, Langlais PR, Hu D, Dong LQ, Liu F. Grb10 mediates insulin-stimulated degradation of the insulin receptor: a mechanism of negative regulation. Am J Physiol Endocrinol Metab. 2006;290:E1262–6. doi: 10.1152/ajpendo.00609.2005.PubMedCrossRefPubMedCentralGoogle Scholar
  16. Stein EG, Gustafson TA, Hubbard SR. The BPS domain of Grb10 inhibits the catalytic activity of the insulin and IGF1 receptors. FEBS Lett. 2001;493:106–11.PubMedCrossRefGoogle Scholar
  17. Vecchione A, Marchese A, Henry P, Rotin D, Morrione A. The Grb10/Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol. 2003;23:3363–72.PubMedCrossRefPubMedCentralGoogle Scholar
  18. Wang J, Dai H, Yousaf N, Moussaif M, Deng Y, Boufelliga A, et al. Grb10, a positive, stimulatory signaling adapter in platelet-derived growth factor BB-, insulin-like growth factor I-, and insulin-mediated mitogenesis. Mol Cell Biol. 1999;19:6217–28.PubMedCrossRefPubMedCentralGoogle Scholar
  19. Wick KR, Werner ED, Langlais P, Ramos FJ, Dong LQ, Shoelson SE, et al. Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)-phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor. J Biol Chem. 2003;278:8460–7. doi: 10.1074/jbc.M208518200.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Yu Y, Yoon SO, Poulogiannis G, Yang Q, Ma XM, Villen J, et al. Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling. Science. 2011;332:1322–6. doi: 10.1126/science.1199484.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Nuzhat N. Kabir
    • 2
  • Lars Rönnstrand
    • 1
  • Julhash U. Kazi
    • 1
    • 2
  1. 1.Division of Translational Cancer Research, Department of Laboratory MedicineLund UniversityLundSweden
  2. 2.Laboratory of Computational BiochemistryKN Biomedical Research InstituteBarisalBangladesh