Mechano-growth factor E-domain modulates cardiac contractile function through 14-3-3 protein interactomes.

Solís C, Thompson WC, Peña JR, McDermott-Roe C, Langa P, Warren CM, Chrzanowska M, Wolska BM, Solaro RJ, Pieter Detombe, Goldspink PH

Frontiers in physiology16 Nov 2022Cited by 1 (Europe PMC)

PMID36467694PMCIDPMC9709209DOI10.3389/fphys.2022.1028345PepBankPUB-36467694

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Summary

In the heart, alternative splicing of the igf-I gene produces two isoforms: IGF-IEa and IGF-IEc, (Mechano-growth factor, MGF). The sequence divergence between their E-domain regions suggests differential isoform function. To define the biological actions of MGF's E-domain, we performed in silico analysis of the unique C-terminal sequence and identified a phosphorylation consensus site residing within a putative 14-3-3 binding motif. To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks. Cardiovascular function was measured using echocardiography and a pressure-volume catheter. At the lowest (2.25 mg/kg/day) and highest (9 mg/kg/day) doses, the peptides produced a depression in systolic and diastolic parameters. However, at 4.5 mg/kg/day the peptides produced opposing effects on cardiac function. Fractional shortening analysis also showed a similar trend, but with no significant change in cardiac geometry. Microarray analysis discovered 21 genes (FDR p Nr4a2) identified as a potential target of peptide regulation. Testing the regulation of the Nr4a family, showed the E-domain peptides modulate Nr4a gene expression following membrane depolarization with KCl in vitro. To determine the potential role of 14-3-3 proteins, we examined 14-3-3 isoform expression and distribution. 14-3-3γ localized to the myofilaments in neonatal cardiac myocytes, the cardiac myocytes and myofilament extracts from the adult heart. Thermal shift analysis of recombinant 14-3-3γ protein showed the S/A¹⁸ peptide destabilized 14-3-3γ folding. Also, the S/A¹⁸ peptide significantly inhibited 14-3-3γ's ability to interact with myosin binding protein C (MYPC3) and phospholamban (PLN) in heart lysates from dobutamine injected mice. Conversely, the S/E¹⁸ peptide showed no effect on 14-3-3γ stability, did not inhibit 14-3-3γ's interaction with PLN but did inhibit the interaction with MYPC3. Replacing the glutamic acid with a phosphate group on Ser 18 (pSer¹⁸), significantly increased 14-3-3γ protein stability. We conclude that the state of Ser 18 phosphorylation within the 14-3-3 binding motif of MGF's E-domain, modulates protein-protein interactions within the 14-3-3γ interactome, which includes proteins involved in the regulation of contractile function.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study14

No result from this study comes from a test of the peptide.

Studies that did not test the peptide alone14

In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking MGF / PEG-MGF.

01AnimalNot a test of MGF / PEG-MGF aloneAnimal study (in vivo)Efficacy outcome
In mice, E-domain peptides at the lowest and highest doses depressed systolic and diastolic parameters of cardiac function.
In plain wordsIn mice, the E-domain peptides at the lowest and highest doses lowered heart pumping and filling measures.
Peptide
MGF / PEG-MGF
Outcome
DecreaseSystolic and diastolic function at 2.25 and 9 mg/kg/day
Study
mousen: not reported in source
Mice given E-domain peptides for 2 weeks
Outcome group
Heart function · Cardiovascular
Source sentences
Summary
At the lowest (2.25 mg/kg/day) and highest (9 mg/kg/day) doses, the peptides produced a depression in systolic and diastolic parameters.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769402
02AnimalNot a test of MGF / PEG-MGF aloneAnimal study (in vivo)Efficacy outcome
In mice, at 4.5 mg/kg/day the two E-domain peptides produced opposing effects on cardiac function.
In plain wordsIn mice, at the middle dose the two E-domain peptides had opposite effects on heart function.
Peptide
MGF / PEG-MGF
Outcome
MixedCardiac function at 4.5 mg/kg/day
Study
mousen: not reported in source
Mice given E-domain peptides for 2 weeks
Outcome group
Heart function · Cardiovascular
Source sentences
Summary
However, at 4.5 mg/kg/day the peptides produced opposing effects on cardiac function.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769403
03AnimalNot a test of MGF / PEG-MGF aloneAnimal study (in vivo)Efficacy outcome
In mice, fractional shortening analysis showed a trend similar to the other cardiac function measures.
In plain wordsIn mice, a heart contraction measure followed a similar pattern to the other heart function results.
Peptide
MGF / PEG-MGF
Outcome
MixedFractional shortening
Study
mousen: not reported in source
Mice given E-domain peptides for 2 weeks
Outcome group
Heart function · Cardiovascular
Source sentences
Summary
Fractional shortening analysis also showed a similar trend, but with no significant change in cardiac geometry.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769404
04AnimalNot a test of MGF / PEG-MGF aloneAnimal study (in vivo)Efficacy outcome
In mice, E-domain peptides caused no significant change in cardiac geometry.
In plain wordsIn mice, the E-domain peptides did not significantly change the size or shape of the heart.
Peptide
MGF / PEG-MGF
Outcome
No significant changeCardiac geometry
Study
mousen: not reported in source
Mice given E-domain peptides for 2 weeks
Outcome group
Heart function · Cardiovascular
Source sentences
Summary
with no significant change in cardiac geometry.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769405
05AnimalNot a test of MGF / PEG-MGF aloneAnimal study (in vivo)Mechanism
In mice, microarray analysis found 21 genes expressed in line with the opposing effects on contractile function at 4.5 mg/kg/day, with Nr4a2 identified as a potential target of peptide regulation.
In plain wordsIn mice, 21 heart genes changed in line with the opposite peptide effects on heart function. Nr4a2 was a possible target.
Peptide
MGF / PEG-MGF
Outcome
MixedCardiac gene expression at 4.5 mg/kg/day
Study
mousen: not reported in source
Microarray of mouse heart after E-domain peptide delivery
Outcome group
Receptor activity and mechanism · Cardiovascular
Measurements
Genes identified
21 genes
4.5 mg/kg/day, FDR p < 0.01
Source sentences
Summary
Microarray analysis discovered 21 genes (FDR p Nr4a2) identified as a potential target of peptide regulation.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769406
06LabNot a test of MGF / PEG-MGF aloneEx vivo tissueMechanism
In heart lysates from dobutamine-injected mice, the S/A18 peptide significantly inhibited 14-3-3 gamma interaction with myosin binding protein C (MYPC3).
In plain wordsIn mouse heart lysates, the S/A18 peptide blocked 14-3-3 gamma from binding myosin binding protein C.
Peptide
MGF / PEG-MGF
Outcome
Decrease14-3-3 gamma interaction with MYPC3 with S/A18 peptide
Study
mousen: not reported in source
Heart lysates from dobutamine-injected mice
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
Also, the S/A¹⁸ peptide significantly inhibited 14-3-3γ's ability to interact with myosin binding protein C (MYPC3) and phospholamban (PLN) in heart lysates from dobutamine injected mice.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769409
07LabNot a test of MGF / PEG-MGF aloneEx vivo tissueMechanism
In heart lysates from dobutamine-injected mice, the S/A18 peptide significantly inhibited 14-3-3 gamma interaction with phospholamban (PLN).
In plain wordsIn mouse heart lysates, the S/A18 peptide blocked 14-3-3 gamma from binding phospholamban.
Peptide
MGF / PEG-MGF
Outcome
Decrease14-3-3 gamma interaction with PLN with S/A18 peptide
Study
mousen: not reported in source
Heart lysates from dobutamine-injected mice
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
Also, the S/A¹⁸ peptide significantly inhibited 14-3-3γ's ability to interact with myosin binding protein C (MYPC3) and phospholamban (PLN) in heart lysates from dobutamine injected mice.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769410
08LabNot a test of MGF / PEG-MGF aloneEx vivo tissueMechanism
The S/E18 peptide did not inhibit 14-3-3 gamma interaction with PLN in heart lysates.
In plain wordsIn mouse heart lysates, the S/E18 peptide did not stop 14-3-3 gamma from binding phospholamban.
Peptide
MGF / PEG-MGF
Outcome
No significant change14-3-3 gamma interaction with PLN with S/E18 peptide
Study
mousen: not reported in source
Heart lysates from dobutamine-injected mice
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
Conversely, the S/E¹⁸ peptide showed no effect on 14-3-3γ stability, did not inhibit 14-3-3γ's interaction with PLN but did inhibit the interaction with MYPC3.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769412
09LabNot a test of MGF / PEG-MGF aloneEx vivo tissueMechanism
The S/E18 peptide did inhibit 14-3-3 gamma interaction with MYPC3 in heart lysates.
In plain wordsIn mouse heart lysates, the S/E18 peptide blocked 14-3-3 gamma from binding myosin binding protein C.
Peptide
MGF / PEG-MGF
Outcome
Decrease14-3-3 gamma interaction with MYPC3 with S/E18 peptide
Study
mousen: not reported in source
Heart lysates from dobutamine-injected mice
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
Conversely, the S/E¹⁸ peptide showed no effect on 14-3-3γ stability, did not inhibit 14-3-3γ's interaction with PLN but did inhibit the interaction with MYPC3.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769413
10LabNot a test of MGF / PEG-MGF aloneIn vitro (cells)Mechanism
In vitro, the E-domain peptides modulated Nr4a gene expression following membrane depolarization with KCl.
In plain wordsIn cells, the E-domain peptides changed the activity of Nr4a genes after the cells were depolarized.
Peptide
MGF / PEG-MGF
Outcome
Direction not reportedNr4a gene expression after KCl depolarization
Study
n: not reported in source
In vitro cells after membrane depolarization with KCl
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
Testing the regulation of the Nr4a family, showed the E-domain peptides modulate Nr4a gene expression following membrane depolarization with KCl in vitro.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769407
11LabNot a test of MGF / PEG-MGF aloneIn vitro (cell-free)Mechanism
In thermal shift analysis, the S/A18 peptide destabilized the folding of recombinant 14-3-3 gamma protein.
In plain wordsIn lab tests, the S/A18 peptide made the 14-3-3 gamma protein less stable.
Peptide
MGF / PEG-MGF
Outcome
Decrease14-3-3 gamma folding stability with S/A18 peptide
Study
n: not reported in source
Recombinant 14-3-3 gamma protein, thermal shift analysis
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
Thermal shift analysis of recombinant 14-3-3γ protein showed the S/A¹⁸ peptide destabilized 14-3-3γ folding.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769408
12LabNot a test of MGF / PEG-MGF aloneIn vitro (cell-free)Mechanism
The S/E18 peptide had no effect on 14-3-3 gamma stability.
In plain wordsIn lab tests, the S/E18 peptide did not change how stable the 14-3-3 gamma protein was.
Peptide
MGF / PEG-MGF
Outcome
No significant change14-3-3 gamma stability with S/E18 peptide
Study
n: not reported in source
Recombinant 14-3-3 gamma protein
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
Conversely, the S/E¹⁸ peptide showed no effect on 14-3-3γ stability, did not inhibit 14-3-3γ's interaction with PLN but did inhibit the interaction with MYPC3.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769411
13LabNot a test of MGF / PEG-MGF aloneIn vitro (cell-free)Mechanism
Replacing the glutamic acid with a phosphate group on Ser 18 (pSer18) significantly increased 14-3-3 gamma protein stability.
In plain wordsIn lab tests, the phosphorylated Ser 18 peptide made the 14-3-3 gamma protein more stable.
Peptide
MGF / PEG-MGF
Outcome
Increase14-3-3 gamma stability with pSer18 peptide
Study
n: not reported in source
Recombinant 14-3-3 gamma protein
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
Replacing the glutamic acid with a phosphate group on Ser 18 (pSer¹⁸), significantly increased 14-3-3γ protein stability.
1 context sentence(design, population, supporting numbers)
Summary · context
To test the functional significance of Ser 18 phosphorylation, phospho-mimetic (S/E¹⁸) and phospho-null (S/A¹⁸) peptides were delivered to mice at different doses for 2 weeks.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769414
14Computer modelNot a test of MGF / PEG-MGF aloneIn silicoMechanism
In silico analysis of the unique C-terminal sequence of MGF's E-domain found a phosphorylation consensus site within a putative 14-3-3 binding motif.
In plain wordsIn computer analysis, the MGF E-domain end contained a site that can carry a phosphate group and may bind 14-3-3 proteins.
Peptide
MGF / PEG-MGF
Outcome
Not applicableSer 18 phosphorylation site in a putative 14-3-3 binding motif
Study
n: not reported in source
In silico sequence analysis of the MGF E-domain C-terminus
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
To define the biological actions of MGF's E-domain, we performed in silico analysis of the unique C-terminal sequence and identified a phosphorylation consensus site residing within a putative 14-3-3 binding motif.
In this study, MGF / PEG-MGF was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking MGF / PEG-MGF.
Show in the study text Report a problemFND-3646769401

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
13 Oct 2026, 21:44 UTC
Study results updated
Version 1
13 Oct 2026, 16:31 UTC
First added · source update from Europe PMC

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