GRB10

Official Full Name

growth factor receptor bound protein 10

Organism

Homo sapiens

GeneID

2887

Background

The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. Overexpression of some isoforms of the encoded protein inhibits tyrosine kinase activity and results in growth suppression. This gene is imprinted in a highly isoform- and tissue-specific manner, with expression observed from the paternal allele in the brain, and from the maternal allele in the placental trophoblasts. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2010]

Synonyms

RSS; IRBP; MEG1; GRB-IR; Grb-10;

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Detailed Information

Grb10, an adapter protein, is a member of the Grb7/Gr10/Grb14 protein family. These proteins interact with a number of receptor tyrosine kinases, impacting a variety of signaling pathways. Specifically, Grb10 has been implicated in the regulation of cell proliferation, metabolism, and apoptosis, among other functions.

Grb10 expression was initially identified in mouse fibroblasts. Although a low level Grb10 mRNA expression was detected in mouse liver, abundant mRNA expression was detected in skeletal muscle, brain, heart, liver, cartilage and in adipose tissue. In humans, higher Grb10 expression was detected in pancreas and skeletal muscle, intermediate expression was detected in brain and cardiac muscle, and lower expression was reported in liver, kidney, lung, placenta, spleen, prostate, ovary, colon, testis and in small intestine. The mRNA expression of Grb10 has been found to be upregulated in primary cervical squamous cell cancers and depletion of Grb10 mRNA by siRNA resulted in marked cell growth inhibition of the cervical squamous cell indicating that Grb10 acts as a survival factor in this disease.

Grb10 is an imprinted gene

Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have important roles in embryonic development, but also postnatal functions including energy homeostasis and behavior. Grb10 is expressed from the maternal chromosome in most tissues in the mouse but is expressed from the paternal allele in a subset of neurons. Maternal expression occurs from the Grb10 major promoter whereas Grb10 paternal expression comes from three downstream alternative promoters. The region surrounding one of these alternative promoters has been identified as an ICR, which exhibits DNA methylation only on the maternal allele in all examined tissues. On the paternal allele, the unmethylated Grb10 ICR is bound by CCCTC-binding factor (CTCF), a multifunctional transcription factor, which is recruited in a DNA methylation-sensitive manner and has been implicated in the regulation of imprinted expression at other loci. Therefore, Grb10 is an imprinted gene with multiple functions and a complex tissue-specific imprinted expression pattern.

Grb10 protein partners

In mouse and human, Grb10 has five major protein domains: a centrally located pleckstrin homology domain (PH), the N-terminal proline-rich region (PR), a Ras-associating domain (RA), a C-terminal Src homology 2 domain (SH2), and the family specific BPS domain, so named because it is between the PH and SH2 domains. Each domain is associated with protein binding partners that define the functions of Grb10 in development and growth (Figure 1).

Figure 1. Grb10 protein partners.

The SH2 domain enables Grb10 to interact with phosphorylated tyrosine residues of other proteins and plays as the recruitment point for a variety of signaling molecules. Many of these proteins are receptors associated with growth, including the growth hormone receptor (GHR) and the insulin receptor (IR). The SH2 domain is key for the role of Grb10 in the mitogen-activated protein kinase (MAPK) pathway, having direct interactions with numerous critical components including MEK1 and RAF1. The BPS domain, specific to the Grb7/10/14 protein family, has also been shown to be important for Grb10’s role in insulin signaling through its binding to IR and additionally binds IGF1R. The BPS domain interacts with the 14-3-3 protein, another protein scaffold with numerous protein partners, and BCL2L11, a proapoptotic scaffold protein required for normal immune function.

The role of Grb10 in insulin receptors signaling

The role of Grb10 in insulin receptors signaling Grb10 was found to be associated with InsR in response to the insulin stimulation and this association resulted in negative regulation of insulin signaling. Similar to InsR, insulin-like growth factor 1 receptor (IRS-1R) associated with Grb10 and the association was mediated through the carboxy-terminus of activated receptor. Nevertheless, unlike other InsR interacting proteins, Grb10 did not associate with the insulin receptor substrate-1 (IRS-1) suggesting that Grb10 plays a unique role in the insulin signaling independent of IRS-1. Although Grb10 has been shown to negatively regulate the insulin signaling, contradictory results have also been reported. Microinjection of the SH2 domain of Grb10 in fibroblasts blocked insulin and IGF-1 induced mitogenesis but had no effect on the EGF-induced mitogenesis suggesting that Grb10 cooperates with insulin in downstream signaling. In addition, in response to IGF-1, PDGF, and insulin, Grb10 potentiates cell proliferation. This biological effect is mediated through the association of Grb10 with Gab1. Overexpression of mouse Grb10a in p6 or other mouse embryo fibroblast cell lines partially blocked insulin-induced transformation but not cell proliferation. Therefore, Grb10 acts differentially in InsR signaling.

References:

Stewart-Cox J E, et al. Distinct physiological and behavioural functions for parental alleles of imprinted Grb10. Nature, 2011, 469(7331):534-538.
Wilkins, Jon F. Genomic Imprinting of Grb10: Coadaptation or Conflict?. PLoS Biology, 2014, 12(2):e1001800.
Kabir N, Kazi J. Grb10 is a dual regulator of receptor tyrosine kinase signaling. Molecular Biology Reports, 2014, 41(4):1985.
Plasschaert R N, Bartolomei M S. Tissue-specific regulation and function of Grb10 during growth and neuronal commitment. Proceedings of the National Academy of Sciences, 2015, 112(22):6841-6847.

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