90745
Pathway
G-Protein Signaling Through Tubby Proteins
Tubby protein is a part of a family of proteins called Tubby Like Proteins (TULP) characterized by 260 amino acids that form a helix-filled barrel structure at the carboxylic acid terminal (Tubby domain). Using its Tubby domain to bind phosphatidylinositol 4,5-bisphosphate (PIP2), Tubby proteins are able to localize on the plasma membrane. Through the receptor mediated activation of G-proteins, the enzyme phospholipase C–beta (PLC-beta) hydrolyses PIP2 releasing tubby from the plasma membrane. This triggers protein translocation of tubby to the nucleus allowing tubby to act as a transcription regulator.
Protein
PW090863
Center
PathwayVisualizationContext91139
1150
1150
#000099
PathwayVisualization90619
90745
G-Protein Signaling Through Tubby Proteins
Tubby protein is a part of a family of proteins called Tubby Like Proteins (TULP) characterized by 260 amino acids that form a helix-filled barrel structure at the carboxylic acid terminal (Tubby domain). Using its Tubby domain to bind phosphatidylinositol 4,5-bisphosphate (PIP2), Tubby proteins are able to localize on the plasma membrane. Through the receptor mediated activation of G-proteins, the enzyme phospholipase C–beta (PLC-beta) hydrolyses PIP2 releasing tubby from the plasma membrane. This triggers protein translocation of tubby to the nucleus allowing tubby to act as a transcription regulator.
Protein
1
261509
11375483
Santagata S, Boggon TJ, Baird CL, Gomez CA, Zhao J, Shan WS, Myszka DG, Shapiro L: G-protein signaling through tubby proteins. Science. 2001 Jun 15;292(5524):2041-50. doi: 10.1126/science.1061233. Epub 2001 May 24.
90745
Pathway
261510
10591637
Boggon TJ, Shan WS, Santagata S, Myers SC, Shapiro L: Implication of tubby proteins as transcription factors by structure-based functional analysis. Science. 1999 Dec 10;286(5447):2119-25.
90745
Pathway
261511
11000483
He W, Ikeda S, Bronson RT, Yan G, Nishina PM, North MA, Naggert JK: GFP-tagged expression and immunohistochemical studies to determine the subcellular localization of the tubby gene family members. Brain Res Mol Brain Res. 2000 Sep 30;81(1-2):109-17.
90745
Pathway
261512
9096357
North MA, Naggert JK, Yan Y, Noben-Trauth K, Nishina PM: Molecular characterization of TUB, TULP1, and TULP2, members of the novel tubby gene family and their possible relation to ocular diseases. Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3128-33.
90745
Pathway
261513
11801719
Ikeda A, Nishina PM, Naggert JK: The tubby-like proteins, a family with roles in neuronal development and function. J Cell Sci. 2002 Jan 1;115(Pt 1):9-14.
90745
Pathway
2
Platelet
CL:0000233
1
Cell
CL:0000000
4
Cardiomyocyte
CL:0000746
8
Beta cell
CL:0000639
3
Neuron
CL:0000540
1
Homo sapiens
9606
Eukaryote
Human
18
Saccharomyces cerevisiae
4932
Eukaryote
Yeast
4
Arabidopsis thaliana
3702
Eukaryote
Thale cress
12
Mus musculus
10090
Eukaryote
Mouse
5
Bos taurus
9913
Eukaryote
Cattle
17
Rattus norvegicus
10116
Eukaryote
Rat
10
Drosophila melanogaster
7227
Eukaryote
Fruit fly
6
Caenorhabditis elegans
6239
Eukaryote
Roundworm
56
Andro
6666
Eukaryote
2
Bacteria
2
Prokaryote
Bacteria
62
Acinetobacter baylyi (strain ATCC 33305 / BD413 / ADP1)
62977
Prokaryote
1
Cytosol
GO:0005829
15
Nucleus
GO:0005634
10
Cell Membrane
GO:0005886
13
Endoplasmic Reticulum
GO:0005783
5
Cytoplasm
GO:0005737
2
Endothelium
BTO:0000393
32
Adrenal Cortex
BTO:0000045
18
Pancreas
BTO:0000988
24
Brain
BTO:0000142
89
16
8
Blood Vessel
BTO:0001102
74
11
16
2
1
2
PW_BS000016
2
1
1
1
PW_BS000002
23
15
1
1
PW_BS000023
14
10
1
PW_BS000014
46
1
1
4
PW_BS000046
160
1
18
1
PW_BS000160
218
15
18
1
PW_BS000024
285
10
4
1
PW_BS000024
1
1
PW_BS000001
128
15
12
1
PW_BS000128
132
1
12
1
PW_BS000132
115
10
12
PW_BS000115
18
13
1
1
PW_BS000018
308
10
1
1
PW_BS000024
8
5
1
1
PW_BS000008
410
15
5
1
PW_BS000115
124
1
5
1
PW_BS000124
405
10
5
PW_BS000115
444
15
17
1
PW_BS000115
118
1
17
1
PW_BS000118
376
10
17
PW_BS000053
485
15
10
1
PW_BS000115
299
1
10
1
PW_BS000024
478
10
10
PW_BS000115
516
15
6
1
PW_BS000115
388
1
6
1
PW_BS000112
209
10
6
PW_BS000024
608
32
1
PW_BS000501
665
18
1
8
PW_BS000508
66
18
5
1
8
PW_BS000066
73
10
1
3
PW_BS000073
85
24
10
1
1
PW_BS000085
599
8
56
PW_BS000501
27
15
1
PW_BS000027
89
2
PW_BS000089
653
1
62
4
PW_BS000508
119
PW_B000119
309
10345
ProteinComplex
1
310
10346
ProteinComplex
1
311
6636
ProteinComplex
1
312
1109
ProteinComplex
1
313
10347
ProteinComplex
1
314
10348
ProteinComplex
1
121
PW_B000121
317
6636
ProteinComplex
1
318
7727
ProteinComplex
1
319
10348
ProteinComplex
1
320
102450
Compound
1
102450
PIP2 [3H]
PIP2 is a phosphatidylinositol bisphosphate. Phosphatidylinositol bisphosphates are acidic (anionic) phospholipids that consist of a phosphatidic acid backbone, linked via the phosphate group to a bisphosphorylated inositol (hexahydroxycyclohexane). Phosphatidylinositol bisphosphates are generated from phosphatidylinositols which are phosphorylated by a number of different kinases that place the phosphate moiety on positions 4 and 5 of the inositol ring, although position 3 can also be phosphorylated. Phosphatidylinositols bisphosphates can have many different combinations of fatty acids of varying lengths and saturation attached at the C-1 and C-2 positions. Fatty acids containing 18 and 20 carbons are the most common. PIP2 has the chemical formula C45H89O19P3, and an average molecular weight of 1029.117. PIP2 is involved in the G-Protein Signaling Through Tubby Proteins Pathway.
[3H][C@]1(O)[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(=O)OC[C@H](COC(=O)CCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCCCC
C45H89O19P3
InChI=1S/C45H89O19P3/c1-3-5-7-9-11-13-15-17-19-21-23-25-27-29-31-33-38(46)59-35-37(61-39(47)34-32-30-28-26-24-22-20-18-16-14-12-10-8-6-4-2)36-60-67(57,58)64-43-40(48)41(49)44(62-65(51,52)53)45(42(43)50)63-66(54,55)56/h37,40-45,48-50H,3-36H2,1-2H3,(H,57,58)(H2,51,52,53)(H2,54,55,56)/t37-,40-,41+,42+,43-,44-,45-/m0/s1/i40T
YSINEOBVJWNAQY-XYEPMSFXSA-N
{[(1S,2S,3S,4R,5S,6S)-4-({[(2S)-2,3-bis(octadecanoyloxy)propoxy](hydroxy)phosphoryl}oxy)-2,3,5-trihydroxy-6-(phosphonooxy)(3-3H)cyclohexyl]oxy}phosphonic acid
1029.117
1028.529315876
-4.67
8
[(1S,2S,3S,4R,5S,6S)-4-{[(2S)-2,3-bis(octadecanoyloxy)propoxy(hydroxy)phosphoryl]oxy}-2,3,5-trihydroxy-6-(phosphonooxy)(3-3H)cyclohexyl]oxyphosphonic acid
0
-5
PW_C102450
PIP23H
1155
Inositol 1,4,5-trisphosphate
HMDB0001498
Intracellular messenger formed by the action of phospholipase C on phosphatidylinositol 4,5-bisphosphate, which is one of the phospholipids that make up the cell membrane. Inositol 1,4,5-trisphosphate is released into the cytoplasm where it releases calcium ions from internal stores within the cell's endoplasmic reticulum. These calcium ions stimulate the activity of B kinase or calmodulin. (PubChem). Inositol 1,4,5-trisphosphate (InsP3) is traditionally considered to be the messenger that initiates the increase and spreading of the activating Ca2+ wave. In line with this hypothesis, recent evidence suggests that the penetrating sperm delivers into mammalian eggs a novel isoform of phospholipase C (PLC), which promotes the formation of InsP3. The mechanism by which the interacting sperm triggers the production of NAADP and subsequently that of InsP3 remains obscure. (PMID: 15362223).
85166-31-0
C01245
439456
16595
inositol_1,4,5-trisphosphate
388562
O[C@@H]1[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@@H](O)[C@@H]1OP(O)(O)=O
C6H15O15P3
InChI=1S/C6H15O15P3/c7-1-2(8)5(20-23(13,14)15)6(21-24(16,17)18)3(9)4(1)19-22(10,11)12/h1-9H,(H2,10,11,12)(H2,13,14,15)(H2,16,17,18)/t1-,2+,3+,4-,5-,6-/m1/s1
MMWCIQZXVOZEGG-XJTPDSDZSA-N
{[(1R,2S,3R,4R,5S,6R)-2,3,5-trihydroxy-4,6-bis(phosphonooxy)cyclohexyl]oxy}phosphonic acid
420.0956
419.962379346
-1.45
9
InsP3
0
-6
FDB022657
1d-myo-inositol 1,4,5-trisphosphate;D-myo-inositol 1,4,5-trisphosphate;Inositol 1,4,5-trisphosphate;1,4,5-insp3;D-myo-inositol-1,4,5-triphosphate;Ins(1,4,5)p3;Insp3;Ip3;1d-myo-inositol 1,4,5-trisphosphoric acid;D-myo-inositol 1,4,5-trisphosphoric acid;D-myo-inositol-1,4,5-triphosphoric acid;Inositol 1,4,5-trisphosphoric acid
PW_C001155
Inotp
274
16
658
2
2037
23
2575
14
2792
46
7387
160
7409
218
12214
285
69344
1
78169
128
78211
132
78516
115
79999
18
80089
308
80237
8
121975
410
122442
124
122511
405
124528
444
125009
118
125081
376
126124
485
126593
299
126664
478
127732
516
128165
388
128241
209
17714
Muscarinic acetylcholine receptor M1
P11229
The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.
CHRM1
1
130960
308
131004
8
2060
5-hydroxytryptamine receptor 2C
P28335
This is one of the several different receptors for 5- hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system
HMDBP02700
HTR2C
AL355812
1
131005
8
1740
Guanine nucleotide-binding protein G(q) subunit alpha
P50148
Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems
HMDBP02022
GNAQ
9q21
U43083
1
5163
14
69323
1
82715
8
82836
308
136005
608
136185
665
136201
66
3618
Gβ
P62873
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 is a guanine nucleotide-binding protein (G protein) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein- effector interaction
HMDBP08398
GNB1
1p36.33
BC005888
1
3812
2
4138
14
4157
73
5010
85
5161
8
69324
1
70006
308
135590
599
136006
608
136181
66
136187
665
17716
Guanine nucleotide-binding protein G(T) subunit gamma-T1
P63211
Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
GNGT1
1
130971
308
131006
8
17717
Tubby protein homolog
P50607
Functions in signal transduction from heterotrimeric G protein-coupled receptors. Binds to membranes containing phosphatidylinositol 4,5-bisphosphate. Can bind DNA (in vitro). May contribute to the regulation of transcription in the nucleus. Could be involved in the hypothalamic regulation of body weight (By similarity). Contribute to stimulation of phagocytosis of apoptotic retinal pigment epithelium (RPE) cells and macrophages.
TUB
1
130974
27
130975
8
130976
14
216
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-1
Q9NQ66
The production of the second messenger molecules diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is mediated by activated phosphatidylinositol-specific phospholipase C enzymes.
HMDBP00222
PLCB1
20p12
AL050315
1
3.1.4.11
2576
14
2790
46
11646
89
69337
1
80090
308
80230
8
136124
653
136191
665
136199
66
10345
Muscarinic acetylcholine receptor M1
1
PW_P010345
18715
17714
10346
5-hydroxytryptamine receptor 2C
1
PW_P010346
18716
2060
6636
Gαq
1
PW_P006636
14377
1740
69304
1
1109
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
1
PW_P001109
1270
3618
1
10347
Guanine nucleotide-binding protein G(T) subunit gamma-T1
1
PW_P010347
18717
17716
10348
Tubby protein homolog
1
PW_P010348
18718
17717
7727
1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta1
1
PW_P007727
15704
216
80557
8
998
Activation
PW_I000998
1995
119
Bound
1
1996
121
Bound
1
999
Activation
PW_I000999
1997
121
Bound
1
1998
10348
ProteinComplex
1
1000
Activation
PW_I001000
1999
121
Bound
1
2000
1155
Compound
1
1001
Activation
PW_I001001
2001
10348
ProteinComplex
1
2002
10348
ProteinComplex
1
529
119
8
90619
875
649487
2949061
876
649488
2949062
877
649489
2949063
878
649490
2949064
879
649491
2949065
880
649492
2949066
530
121
8
90619
439
2169493
2949068
881
649493
2949069
882
649494
2949070
883
649495
2949072
2169493
102450
8
3
false
818
318
10
regular
100
100
2169586
1155
8
3
false
818
478
10
regular
100
120
763178
17714
8
80
false
203
88
8
subunit
regular
200
130
763179
2060
8
80
false
348
93
8
subunit
regular
200
130
763180
1740
8
2
false
208
203
8
subunit
regular
150
70
763181
3618
8
2
false
333
203
8
subunit
regular
150
70
763182
17716
8
2
false
203
263
8
subunit
regular
150
70
763183
17717
8
2
false
328
263
8
subunit
regular
150
70
763184
1740
8
2
false
693
263
8
subunit
regular
150
70
763185
216
8
2
false
823
263
8
subunit
regular
150
70
763186
17717
8
2
false
693
328
8
subunit
regular
150
70
763204
17717
8
2
false
423
498
8
subunit
regular
150
70
763566
17717
8
2
false
423
743
8
subunit
regular
150
70
649487
10345
90619
8
761561
763178
649488
10346
90619
8
761562
763179
649489
6636
90619
8
761563
763180
649490
1109
90619
8
761564
763181
649491
10347
90619
8
761565
763182
649492
10348
90619
8
761566
763183
649493
6636
90619
8
761567
763184
649494
7727
90619
8
761568
763185
649495
10348
90619
8
761569
763186
649513
10348
90619
8
761587
763204
649863
10348
90619
8
761949
763566
2949061
M-302 -297 L-302 -247 L-252 -297 z
10
true
18
2949062
M-302 -237 L-302 -187 L-252 -237 z
10
true
18
2949063
M-302 -177 L-302 -127 L-252 -177 z
10
true
18
2949064
M-302 -117 L-302 -67 L-252 -117 z
10
true
18
2949065
M-302 -57 L-302 -7 L-252 -57 z
10
true
18
2949066
M-302 3 L-302 53 L-252 3 z
10
true
18
2949067
M478 298 C508 298 593 273 623 273
149
true
18
2949068
M688 318 L688 368 L738 318 z
10
true
18
2949069
M688 258 L688 308 L738 258 z
10
true
18
2949070
M828 258 L828 308 L878 258 z
10
true
18
2949072
M968 258 L968 308 L1018 258 z
10
true
18
2949073
M693 298 C663 298 508 298 478 298
149
false
18
true
M 489.44685504416486 76.26155629629604 L 474.5 75 L 480.88088772118584 88.57513432307834
false
2949151
M498 498 C498 468 908 505.5 908 475.5
149
true
18
true
M 890.9468550441649 444.92821279043665 L 876 443.6666564941406 L 882.3808877211858 457.24179081721894
false
2949152
M693 363 C675 364 517 362 498 362 C498 382 498 472 498 498
149
false
18
true
M 1660.5 817.5096189432334 L 1668 830.5 L 1675.5 817.5096189432334
false
2949197
M868 478 C868 448 908 518 908 488
149
true
18
true
M 890.9468550441649 444.92821279043665 L 876 443.6666564941406 L 882.3808877211858 457.24179081721894
false
2949198
M868 418 C868 448 868 448 868 478
149
false
18
true
M 1660.5 830.0096189432334 L 1668 843 L 1675.5 830.0096189432334
false
2950845
M498 568 C498 598 493 703 493 733
149
true
18
2950846
M498 743 C498 713 498 598 498 568
149
false
18
true
M 890.9468550441649 903.5948692845773 L 876 902.3333129882812 L 882.3808877211858 915.9084473113596
false
2950863
M498 813 C501 851 549 842.3333129882812 592 846.3333129882812
147
false
18
true
M 1380.7876739789924 1574.1710935776766 L 1390 1562.3333129882812 L 1375.1420182746535 1560.2740949208421
false
2500
998
90619
8
652
529
2949067
Left
653
530
2949073
Right
2501
999
90619
8
654
530
2949152
Left
3094
649513
2949151
Right
2502
1000
90619
8
655
530
2949198
Left
770
2169586
2949197
Right
2503
1001
90619
8
3095
649513
2950845
Left
3096
649863
2950846
Right
64017
2950863
146778
400
617
1.3
1.3
0
2
14
327
267
301182
M124 261 C124 211 174 161 224 161 C436 161 713 161 925 161 C975 161 1025 211 1025 261 C1025 462 1025 724 1025 925 C1025 975 975 1025 925 1025 C713 1025 436 1025 224 1025 C174 1025 124 975 124 925 C124 724 124 462 124 261
1
true
6
901.0
864.0
359086
235
Gene Regulation
590
805
20
1.0
1.0
200
15
361637
235
Nucleus
538
639
20
1.3
1.3
200
15
361638
235
Cytoplasm
188
377
20
1.3
1.3
200
15