Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Nuzhat N. Kabir
  • Lars Rönnstrand
  • Julhash U. Kazi
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101665


 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


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.


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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