Analysis
Supplement - Global Graph Distribution Analysis of the Receptor Interactome
As described in the main text and Supplement S2, the receptor interactome includes interactions for each human membrane receptor in the HPMR database [1]. Totally, there are 904 receptor genes and for each one of them, we identified their potential PPI partners from all possible human genes, 24380 human genes based on the NCBI. The thresholded graph contains ~9100 edges, which relates to 559 membrane receptors and 1750 non-receptors. Note: interactions between non-receptor genes are not evaluated and considered in this graph. Visualizations of this graph are shown in Supplement S4. Biclustering analysis of this predicted receptor interactome is in another Supplement webpage and the graph global distribution studies are included here.
From a graph analysis perspective, the receptor interactome could be treated as an undirected graph, with nodes representing proteins and edges as interactions. This graph combines two networks: the first is an interaction graph between receptors and the second is a bipartite graph between receptors and non-receptors (genes not in HPMR database [1]). The global graph patterns are very important in analyzing the biological networks based on the previously studies [2]. Here we made a series of distribution analysis.
All analyses of the predicted receptor
interactome are compared with the respective properties of the known receptor
interactions retrieved from the HPRD [3].
1. Hubs in the receptor
interactome – predicted and known
We identified those receptors having the
largest number of protein binding partners as ‘hubs’. Since GPCR and type I
receptors have very different properties, we list the hubs of these two
families of receptors separately.
GPCR Hubs: GPCR hubs refer those GPCR’s having the most
gene partners among all GPCR. The top 20 largest GPCR hubs are shown in Table 1. Entries in
the table are ordered by the number of protein partners that each GPCR
interacts with. We notice that several of the GPCR hubs are from the chemokine
receptor family. Part of this table is also provided in Table 2 of the main
text.
|
Table 1
GPCR
hubs with the highest number of binding partners: GPCR
hub refers those GPCR’s having the most gene partners among all GPCR. Entries
are ordered by the number of protein partners that each GPCR interacts with.
The top 20 largest GPCR hubs are shown. |
||||||
|
Gene ID |
Gene Symbol |
Partner Size (Predicted) |
Partner Size (HPRD) |
Receptor Partner Size (Predicted) |
Receptor Partner Size (HPRD) |
Gene Receptor Family |
|
976 |
CD97 |
60 |
1 |
17 |
0 |
7TM|B|Orphan|CD97 |
|
9620 |
CELSR1 |
60 |
0 |
28 |
0 |
7TM|B|Orphan|CD97 |
|
267 |
AMFR |
49 |
3 |
6 |
0 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
1952 |
CELSR2 |
39 |
0 |
21 |
0 |
7TM|B|Orphan|CD97 |
|
2833 |
CXCR3 |
24 |
0 |
5 |
0 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
1234 |
CCR5 |
22 |
21 |
4 |
2 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
2149 |
F2R |
22 |
7 |
3 |
1 |
7TM|A|Polypeptide|Proteinase-activated/thrombin |
|
1235 |
CCR6 |
20 |
3 |
3 |
0 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
1230 |
CCR1 |
20 |
9 |
3 |
0 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
135 |
ADORA2A |
18 |
2 |
2 |
1 |
7TM|A|Nucleotide|Adenosine |
|
1910 |
EDNRB |
18 |
6 |
3 |
0 |
7TM|A|Polypeptide|Bombesin/Gastrin |
|
3579 |
IL8RB |
18 |
11 |
1 |
0 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
1233 |
CCR4 |
16 |
6 |
4 |
0 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
2550 |
GABBR1 |
15 |
3 |
0 |
0 |
7TM|C|Amine |
|
1238 |
CCBP2 |
13 |
14 |
0 |
0 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
1241 |
LTB4R |
13 |
1 |
5 |
0 |
7TM|A|Lipid|Leukotriene_B4 |
|
2151 |
F2RL2 |
12 |
5 |
1 |
0 |
7TM|A|Polypeptide|Proteinase-activated/thrombin |
|
3577 |
IL8RA |
12 |
9 |
2 |
0 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
1232 |
CCR3 |
11 |
12 |
0 |
0 |
7TM|A|Polypeptide|Chemokine/interleukin |
|
6608 |
SMO |
10 |
2 |
5 |
2 |
7TM|Frizzled_Smo |
Type I Receptor Hubs:
Type I receptors hubs refers to
those type I receptors having the largest number of protein binding partners
among type I receptors. The entries in Table
2 are ordered by the number of gene partners of each
respective type I receptor. Part of this table is in Table 1 of the main text.
|
Table
2
Type
I receptor hubs with the highest number of binding partners: Type
I receptors hubs refer to those type I receptors having the largest number of
protein binding partners among type I receptors. The top 20 entries are
shown. Entries are ordered by the number of gene partners of each respective
type I receptor. |
||||||
|
GeneID |
Gene Symbol |
Partner Size (Predict) |
Partner Size (HPRD) |
ReceptorPartner Size (Predict) |
ReceptorPartner Size (HPRD) |
Gene Receptor Family |
|
7048 |
TGFBR2 |
217 |
21 |
29 |
5 |
SerThrK|Type |
|
3688 |
ITGB1 |
191 |
44 |
60 |
15 |
Integrins|ITB-4 |
|
2022 |
ENG |
181 |
10 |
35 |
4 |
Other |
|
5792 |
PTPRF |
172 |
13 |
61 |
2 |
RPTP|RPTPUI5 |
|
2260 |
FGFR1 |
172 |
13 |
45 |
0 |
RTK|FGR |
|
3949 |
LDLR |
163 |
9 |
28 |
0 |
LDLLRP |
|
657 |
BMPR1A |
161 |
14 |
19 |
2 |
SerThrK|ALK |
|
659 |
BMPR2 |
155 |
10 |
26 |
2 |
SerThrK|Type |
|
7046 |
TGFBR1 |
155 |
25 |
21 |
4 |
SerThrK|ALK |
|
2064 |
ERBB2 |
153 |
32 |
45 |
4 |
RTK|ERBB/EGF |
|
3480 |
IGF1R |
150 |
26 |
50 |
0 |
RTK|INSULIN-R |
|
1436 |
CSF1R |
149 |
11 |
44 |
0 |
RTK|VEGF/PDGF |
|
1956 |
EGFR |
147 |
91 |
45 |
6 |
RTK|ERBB/EGF |
|
4853 |
NOTCH2 |
131 |
9 |
35 |
0 |
Notch |
|
2050 |
EPHB4 |
127 |
1 |
51 |
0 |
RTK|EPHRIN |
|
4851 |
NOTCH1 |
127 |
17 |
42 |
0 |
Notch |
|
2321 |
FLT1 |
124 |
6 |
46 |
1 |
RTK|VEGF/PDGF |
|
5159 |
PDGFRB |
122 |
28 |
44 |
4 |
RTK|VEGF/PDGF |
|
1969 |
EPHA2 |
119 |
12 |
52 |
0 |
RTK|EPHRIN |
|
5754 |
PTK7 |
117 |
0 |
52 |
0 |
RTK |
Receptor Core Hubs: We also used the number of receptor only partners as a criterion to search for receptor-receptor interaction hubs in our predicted receptor interactome. Receptor hub here refers to a hub in the receptor to receptor subgraph. The top 20 most highly ranked receptors are listed in Table 3. They are ordered by the number of the receptor interaction partners. We found that all of them belonged to the Type I receptor family.
|
Table
3
Receptor
core hubs binding to the largest number of receptor partners: We used
the number of receptor only partners as a criterion to search for
receptor-receptor interaction hubs in our predicted receptor interactome.
Receptor hub in this subsection refers to a hub in the receptor versus
receptor subgraph. Here the top 20 ranked receptors
are listed. They are ordered by increasing size of the number of receptor
binding partners. All of them belonged to the Type I receptor family. |
||||||
|
Gene ID |
Gene Symbol |
Receptor Partner Size (Predict) |
Receptor Partner Size (HPRD) |
GPCR Partner Size (Predict) |
GPCR Partner Size (HPRD) |
Receptor family |
|
5792 |
PTPRF |
65 |
2 |
3 |
0 |
RPTP|RPTPUI5 |
|
3688 |
ITGB1 |
64 |
15 |
6 |
0 |
Integrins|ITB-4 |
|
2050 |
EPHB4 |
51 |
0 |
1 |
0 |
RTK|EPHRIN |
|
5754 |
PTK7 |
51 |
0 |
1 |
0 |
RTK |
|
3480 |
IGF1R |
49 |
0 |
0 |
0 |
RTK|INSULIN-R |
|
1436 |
CSF1R |
47 |
0 |
5 |
0 |
RTK|VEGF/PDGF |
|
2321 |
FLT1 |
47 |
1 |
1 |
0 |
RTK|VEGF/PDGF |
|
5159 |
PDGFRB |
47 |
4 |
0 |
1 |
RTK|VEGF/PDGF |
|
780 |
DDR1 |
47 |
0 |
2 |
0 |
RTK|DDR |
|
2260 |
FGFR1 |
46 |
0 |
2 |
0 |
RTK|FGR |
|
1956 |
EGFR |
45 |
6 |
0 |
0 |
RTK|ERBB/EGF |
|
2064 |
ERBB2 |
44 |
4 |
1 |
0 |
RTK|ERBB/EGF |
|
3643 |
INSR |
44 |
2 |
1 |
0 |
RTK|INSULIN-R |
|
4919 |
ROR1 |
44 |
0 |
1 |
0 |
RTK|ROR |
|
4920 |
ROR2 |
43 |
0 |
1 |
0 |
RTK|ROR |
|
1969 |
EPHA2 |
41 |
0 |
1 |
0 |
RTK|EPHRIN |
|
4233 |
MET |
41 |
0 |
0 |
0 |
RTK|MET |
|
2044 |
EPHA5 |
40 |
0 |
1 |
0 |
RTK|EPHRINs |
|
558 |
AXL |
40 |
0 |
0 |
0 |
RTK|TYR/MER/UFO |
|
2065 |
ERBB3 |
39 |
3 |
0 |
0 |
RTK|ERBB/EGF |
|
5156 |
PDGFRA |
39 |
3 |
0 |
0 |
RTK|VEGF/PDGF |
2. Degree distribution of
the receptor interactome – predicted and known
Previous studies [2] show that biological networks are usually obeying a
power law distribution. This is also true for our receptor interactome. In the
following, we report a series of degree distributions for receptors with
respect to different types of interaction partners. The receptor binding
partners are all possible human proteins, or just receptors, or non-receptor
proteins. Receptors can be further divided into type I and II receptors. We
generated all possible degree distribution figures for these comparisons, and these
are available from the authors upon request. Here, we only discuss a subset
that demonstrates the most striking observation, namely that in the predicted
receptor interactome, type I receptors display much more receptor partners as
compared to GPCRs suggesting that GPCR heterooligomerization is rare compared
to type I receptor heterooligomerization.
Receptor degree distributions with
respect to all possible binding partners: Figure S7.1 compares the degree distribution of each receptor with
all possible partners. Comparisons were made for both, the predicted and the
HPRD receptor interactome graphs. The
distributions are seen to obey a power-law [2].
|
|
|
Figure 1
Degree distribution of receptors
in terms of all possible partners. a.
Histogram of the number of binding partners each receptor has in the
predicted receptor interactome. b. Histogram of the number of binding
partners each receptor has in the HPRD [3]. |
Average degree analysis: We further analyzed the average interaction degree of the receptors with other proteins in the graph.
|
Table 4
Average
degrees of receptors with other proteins. The mean or median interaction degree of
those receptors who have at least one interactions partner is listed. |
||
|
Number of interaction partners a receptor
has: |
Predicted |
HPRD |
|
Median degree |
4 |
3 |
|
Mean degree |
18.3 |
5.7 |
GPCR
degree distribution in terms of possible receptors partners: We compared the degree
distributions of each GPCR receptor with respect to their receptors partners in
the predicted and HPRD receptor interactome graphs. The results are shown in
Fig. 2. The two distributions are quite similar to each other: GPCR to receptor
interactions are sparse in both predicted and known receptor interaction
graphs.
|
|
Figure 2
Degree distribution of GPCRs with other receptors. a. Histogram
of the number of receptor partners each GPCR has in the predicted receptor interactome.
b. Histogram of the number of receptor partners each GPCR has in the HPRD [3].
|
Type I receptors degree distribution
in terms of possible receptors partners: In Figure 3 , we compare the degree distribution of each type I
receptor with respect to their receptors partners. Comparisons were made in
both predicted and HPRD receptor interactome graphs. The two distributions are
quite different. In the predicted receptor interactome, type I receptors have
much more receptor partners compared to what is provided in the HPRD [3].
|
|
Figure 3
Degree distribution of Type I receptors in terms of the
receptor interaction partners. a. Histogram of
number of receptor partners each Type I receptor has in the predicted
receptor interactome. b. Histogram of number of receptor partners each Type I
receptor has in the HPRD [3]
|
Based on the above analysis we conclude that in the predicted the receptor interactome, type I receptors interact more commonly with other receptor partners than do the GPCR’s.
3. Genes highly interacting with GPCR genes in the receptor
interactome
Since GPCR’s are not interacting extensively with other receptors, we investigated in more detail interactions of GPCR’s with non-receptor proteins. Table S7.5 lists the top 20 ranked genes that are not listed in the HPMR [1] (our definition of non-receptor proteins) based on the largest number of predicted GPCR receptor partners. Several of these are chemokine related.
|
Table
5
Genes
highly interacting with GPCR: Top 20 ranked
genes that are not in HPMR [1] receptor list and are ranked high based on the
number of predicted GPCR receptor partners. |
|||
|
Gene ID |
Gene Symbol |
GPCR Partner Sizes (Predicted) |
GPCR Partner Sizes (HPRD) |
|
2771 |
GNAI2 |
14 |
16 |
|
3458 |
IFNG |
10 |
0 |
|
60675 |
PROK2 |
9 |
0 |
|
2335 |
FN1 |
8 |
1 |
|
6347 |
CCL2 |
8 |
5 |
|
6352 |
CCL5 |
8 |
6 |
|
1009 |
CDH11 |
7 |
0 |
|
6348 |
CCL3 |
7 |
4 |
|
2769 |
GNA15 |
6 |
12 |
|
2773 |
GNAI3 |
6 |
5 |
|
2776 |
GNAQ |
6 |
16 |
|
3576 |
IL8 |
6 |
3 |
|
3627 |
CXCL10 |
6 |
0 |
|
408 |
ARRB1 |
6 |
7 |
|
6351 |
CCL4 |
6 |
3 |
|
6356 |
CCL11 |
6 |
4 |
|
6355 |
CCL8 |
5 |
5 |
|
6363 |
CCL19 |
5 |
2 |
|
6387 |
CXCL12 |
5 |
1 |
|
6774 |
STAT3 |
5 |
1 |