Grb-10: the "Hulk-Protein"
Proteins

Author: Mirko Ippolito
Date: 19/10/2013

Description

DEFINITION

Grb-10 it's a protein belonging to Growth Factor Receptor-bound proteins and cause of its specifically action in bounding the Insuline Receptors ,and like-ones (IGFR), it is also called Insulin receptor-binding protein Grb-IR. The protein family, which Grb-10 belongs to, are adaptor proteins interacting with Tyrosin Kinase Receptors such as, in this case, Growth Factor ones.
It has been discovered mutated or deleted in mice with enormous muscle growth. Studies have revealed its nature as inhibitor of insulin receptor and as inhibitor of Insuline-like growth factor receptors.

THE GENE

In humans its gene-location is 7p12.1. In particular, Location-base-pair starts at 50657760 and ends at 50800050 bp from pter (atlasgeneticsoncology.org).
We also know, thanks to Monk et al.2009, that the gene includes 19 coding exons and 7 non-coding ones.

DatabaseLink
WikigenesGrb-10
GeneCardsGrb-10
UniProtGrb-10
NCBIGrb-10
HUGOGrb-10

About its inheritance we know that is an imprinted gene with a species-specific pattern; Genomic Imprinting is a form of epigenetic inheritance in mammals in which a small subset of autosomal genes show parental-allele-specific expression.
Human GRB10 is expressed almost exclusively from the paternal allele in the fetal brain, it has maternal-specific expression of one isoform (γ1) in skeletal muscle, and biallelic one in all other tissues.

(OxfordJournals-2003)

CHEMICAL STRUCTURE AND IMAGES

Grb-10 is a protein of 594 AA with a molecular weight of 67231 Da and basal isoelectric point of 8.06.
Moreover, cDNA studies reveal that the protein contains:

  • an SH2 domain, which interacts with phosphotyrosine of several proteins;
  • a pleckstrin-homology (PH) domain of 124 aa (except for an isoform which contains only 85 aa) probably with important role in targeting Grb10 to the mitochondria;
  • a BPS (Between PH and SH2) domain which binds to the activated insulin and/or IGF-1 receptors;
  • a Ras -associating (RA) domain.

(OMIM; Structural and functional studies of the Ras-associating and pleckstrin-homology domains of Grb10 and Grb14- 2009;
atlasgeneticsoncology).

Protein Aminoacids Percentual

SYNTHESIS AND TURNOVER

The image below illustrates the normal expression of Grb-10 in differents Human tissues.

During its synthesis it's possible to assist at various alternative splicing which brings the formation of 4 principal kind of protein isoforms :

IsoformAliasaa
hGrb10-βGrb-IR548
hGrb10-γGrb10/IR-SV1536
hGrb10-εKIAA0207588
hGrb10-ζhGrb10-ζ594

(Grb10 and Grb14: enigmatic regulators of insulin action – and more? -2005)
Note that these splice variants share a similar basal structure.

CELLULAR FUNCTIONS

As we say before, Grb-10 belongs to adapter proteins which interacts with tyrosine kinase receptors on cell surface and in this way modulates specific signaling pathways. The insulin and insulin-like growth factor (IGF1R) receptors are the two principal TKRs involved with Grb-10.
When bounds its targer it inhibits the related signaling pathways blocking the cell growth and it can do this in two different ways: the first one is the interference with the signaling pathway, and the second one is increasing TKRs degradation by proteasome or lysosome.
(Grb10 and Grb14: enigmatic regulators of insulin action – and more? -2005)

There are evidences revealing that mTOR, which is a fundamental protein regulating cell growth, phosphorylates and stabilizes Grb-10 so inhibiting the uncontrolled cell growth; in fact different cancers showed a downregulation of Grb-10 exhalting is role as tumor suppressor.

(genecards; Phosphoproteomic analysis identifies Grb10 as an mTORC1 substrate that negatively regulates insulin signaling-2011)

REGULATION

By phosphorylation

Grb-10 is subjected at post-translational modification by phosphorylation on serine residues, upon EGF, FGF and PDGF stimulation, and at Tyr-67 by TEC(gene) .
Moreover, for its functioning Grb-10 receives a phosphorylation by mTORC1 protein which stabilizes and activates it.

Controlling its expression

A different way to regulate its functioning within the cells it's controlling its expression. Thanks to Lowenna J. Holt and Kenneth Siddle -2005 we know that VEGF is a positive regulator of its transcription and that Grb-10 itself promotes a positive feedback increasing the VEGF receptors in the cells where it's expressed.

THERAPEUTIC USES

Muscle Growth

Recent studies in mice with a disruption of the Grb10 gene reveal that these mice have an improved whole-body glucose tolerance and insulin sensitivity, as well as increased muscle mass and reduced adiposity. The interesting thing of this studies is that the muscle enlargement seen in these mice is not due to increased myofiber size (Hypertrophy), but rather an increase in myofiber number and so it's a case of hyperplasia but there's no alteration or metabolic changing in their fibers respect normal ones.

"In addition, Grb10-ablated muscle from adult mice shows coordinate gene changes that oppose those of muscle wasting pathologies, highlighting Grb10 as a potential therapeutic target for these conditions". (Grb10 regulates the development of fiber number in skeletal muscle-2010)
Mice KO for Grb-10 demonstrate that increased body weight of Grb10-deficient mice is maintained throughout life since their birth.

Obviously this is an interesting discovery because of its implication if scientists found a way to use these information for a human therapeutic strategies to treat muscle injury and disease, such as for example Muscular Dystrophy.

(Mice with a Disruption of the Imprinted Grb10 Gene Exhibit Altered Body Composition, Glucose Homeostasis, and Insulin Signaling during Postnatal Life-2007; medmonash)

Insulin Resistance and Pancreatic Role of Grb-10

Insulin Resistance is a pathologic situation in which we can observe an alteration of the physiological glucose homeostasis because of a lower response mediated by the insulin receptors which, in normal conditions, mediate the glucose uptake by cells so to reduce its blood concentration; from that it follows a condition of hyperglicemia that is a possible cause of Type II Diabetes and Metabolic Syndrome.

The role of Grb-10 in these pathways is a bit controversial. Numerous studies revealed that it downregulates not only the insulin-receptor function in glucose uptake, but also the related pathways in glycogen synthesis; however, there are a few studies that showed instead a positive regulation. Notwithstanding that, scientists think the negative role of Grb-10 be the right one, accordingly with the results in tissue growth and increased insulin sensitivity.
In addition to the insulin resistance, another feature of Type II Diabetes is a decrease of Insulin secretion. Researches on mice show that Grb10 is an important regulator of Pancreatic β-cell proliferation where it's expressed a lot; if we reduce the expression of Grb10 here we see increasing of β-cell mass and insulin secretion but also the reducing of β-cel apoptosis. So this could be a therapeutic use not only for type II diabetes but also for type I.

(Peripheral Disruption of the Grb10 Gene Enhances Insulin Signaling and Sensitivity In Vivo-2007;
Disruption of Growth Factor Receptor–Binding Protein 10 in the Pancreas Enhances β-Cell Proliferation and Protects Mice From Streptozotocin-Induced β-Cell Apoptosis-2012;
New Role for Grb10 Signaling in the Pancreas-2012)

Grb-10 and Silver–Russell Syndrome (SRS)

The Silver-Russell Syndrome is characterized by prenatal and postnatal growth retardation and dysmorphic features. In particular usually the phenotype is related to the presence of a mutation in 10% of patients, specifically an Uniparental Disomy, in an imprinted gene on chromosome 7 probably responsible for growth.
Human Grb-10 belongs, as it was said before, on chromosome 7, and because it has a suppressive effect on growth, through its interaction with either the IGF-I receptor or the GH receptor, it is a candidate gene for this syndrome.
In particular, in the literature of SRS we can read about a study in which two patients with SRS were shown to have a maternally derived duplication of 7p11-p13; since Grb-10 is a maternally expressed gene belonging of chromosome 7, and since it was found overexpressed in patients with RSS having maternal UPD7, because of Grb-10 inhibiting action on IGF-I receptor the resulting overexpression would confirm a similar phenotype, further worsened if the patients had haploinsufficiency of the IGF-1 receptor.
So it would contributes to the pathologic phenotype.

(Imprinting of Human GRB10 and Its Mutations in Two Patients with Russell-Silver Syndrome-2000)

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