Zodiac (Case 5): A Potential Drug Target for Multiple Types of Cancers: PIK3R1

This is the 5th-article of a blog series aiming to introduce Zodiac, a comprehensive tool that reveals genetic interactions in cancer by big-data computation. An introduction of Zodiac is in the 1st article here.

Large-scale cancer sequencing projects have identified PIK3R1 as one of the most commonly mutated genes across different tumors by Cheung et al. (2014). The authors also show the intricate relationship among PIK3R1, ERK (MAPK1), and JNK (MAPK8). An independent set of upstream mutations also exhibit oncogenic activity by altering stability of PTEN and by activating the MAPK pathway.

The circos plot in Figure 1 shows the results from Zodiac (Zhu et al., 2015, http://www.compgenome.org/zodiac). It is obtained by typing the four gene names  PIK3R1 MAPK1 MAPK8 PTEN in the Zodiac search bar.

four-gene

The plot shows that the GE (gene expression) of PIK3R1 positively connect with the GE of MAPK1 and MAPK8; the PE (protein expression) of PIK3R1 positively connects with the PE of PTEN. This confirms existing knowledge about PIK3R1.

circos

Typing PIK3R1 in Zodiac will return all the significant genetic interactions between any other genes and PIK3R1. Let’s take a look at the top 20 genes that positively connect with PIK3R1 in terms of GE-GE interaction.

Side Note: We added a “Full Description List” button (see figure below) and clicking it you get all the NCBI descriptions of the top genes returned by Zodiac.

describe

The top gene is GRM3. Below is the NCBI description:

  • GRM3 L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.

Apparently, GRM3 is involved in most aspects of brain functions. Strikingly, in Zodiac, the beta-value of GRM3 and PIK3R1 is 21.01. This is a very large score as a score greater than 5 is usually considered large in our statistical model. It means there is a 21-fold incremental chance that the gene expression of GRM3 will be disrupted if the gene expression of PIK3R1 is disrupted. For example, a somatic mutation in PIK3R1 might alter its expression, which would highly likely alter the expression of GRM3.

It has been known that PIK3R1 is known to be a potential drug target of glioblastoma (Weber et al., 2011). Having a strong interaction with GRM family might explain the mechanism of PIK3R1 in brain tumor development.

Next I show a selected list of genes among the 20 ones that interact with PIK3R1. Apparently, these genes are important by just looking at their descriptions.

  • N4BP2 This gene encodes a protein containing a polynucleotide kinase domain (PNK) near the N-terminal region, and a Small MutS Related (Smr) domain near the C-terminal region. The encoded protein can bind to both B-cell leukemia/lymphoma 3 (BCL-3) and neural precursor cell expressed, developmentally downregulated 4, (Nedd4) proteins. This protein binds and hydrolyzes ATP, may function as a 5′-polynucleotide kinase, and has the capacity to be a ubiquitylation substrate. This protein may play a role in transcription-coupled DNA repair or genetic recombination.
  • RPS6KA3 This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation.
  • PDZD2 Proteins containing PDZ domains have been shown frequently to bind the C-termini of transmembrane receptors or ion channels. They have also been shown to bind to other PDZ domain proteins and could possibly be involved in intracellular signalling. The protein encoded by this gene contains six PDZ domains and shares sequence similarity with pro-interleukin-16 (pro-IL-16). Like pro-IL-16, the encoded protein localizes to the endoplasmic reticulum and is thought to be cleaved by a caspase to produce a secreted peptide containing two PDZ domains. In addition, this gene is upregulated in primary prostate tumors and may be involved in the early stages of prostate tumorigenesis.
  • ARID4B This gene encodes a protein with sequence similarity to retinoblastoma-binding protein-1. The encoded protein is a subunit of the histone deacetylase-dependant SIN3A transcriptional corepressor complex, which functions in diverse cellular processes including proliferation, differentiation, apoptosis, oncogenesis, and cell fate determination. The gene product is recognized by IgG antibody isolated from a breast cancer patient and appears to be a molecular marker associated with a broad range of human malignancies.

Lastly, let me end by pointing to the following three genes, DMXL1 SESN3 REL, which are all among the top 20 genes interacting with PIK3R1 in terms GE-GE. These genes are related to hematopoietic cell development, blood glucose, and proliferation of B lymphocytes. Therefore, PIK3R1 might also play a role in liquid cancer.

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3 thoughts on “Zodiac (Case 5): A Potential Drug Target for Multiple Types of Cancers: PIK3R1

    • Thanks, Fred! This is good to know. I am not surprised there are additional papers supporting roles of PIK3R1 in cancer. I guess what Zodiac can provide is potential interacting genes that might explain the mechanism with which PIK3R1 affects phenotypes.

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      • Fred Boehm says:

        Yes, I agree. I think it’s cool that among the genes that Zodiac identified are the three that you point to – DMXL1 SESN3 REL – that suggest the roles that you mentioned. In searching google scholar for PI3KR1, I think that there was a report that suggested a connection to insulin sensitivity. It may very well be mediated by the gene that you mention in the last paragraph.

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