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Cited by 115Protein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysEstrogen and related hormone effects

A mitochondrial kinase complex is essential to mediate an ERK1/2-dependent phosphorylation of a key regulatory protein in steroid biosynthesis

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Poderoso, Cecilia, Converso, Daniela P., Maloberti, Paula, Duarte, Alejandra, Neuman, Isabel, Galli, Soledad, Maciel, Fabiana Cornejo, Paz, Cristina +3 more·2008·PLoS ONE
DOI 10.1371/journal.pone.0001443PMC PMC2175533
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Abstract

ERK1/2 is known to be involved in hormone-stimulated steroid synthesis, but its exact roles and the underlying mechanisms remain elusive. Both ERK1/2 phosphorylation and steroidogenesis may be triggered by cAMP/cAMP-dependent protein kinase (PKA)-dependent and-independent mechanisms; however, ERK1/2 activation by cAMP results in a maximal steroidogenic rate, whereas canonical activation by epidermal growth factor (EGF) does not. We demonstrate herein by Western blot analysis and confocal studies that temporal mitochondrial ERK1/2 activation is obligatory for PKA-mediated steroidogenesis in the Leydig-transformed MA-10 cell line. PKA activity leads to the phosphorylation of a constitutive mitochondrial MEK1/2 pool with a lower effect in cytosolic MEKs, while EGF allows predominant cytosolic MEK activation and nuclear pERK1/2 localization. These results would explain why PKA favors a more durable ERK1/2 activation in mitochondria than does EGF. By means of ex vivo experiments, we showed that mitochondrial maximal steroidogenesis occurred as a result of the mutual action of steroidogenic acute regulatory (StAR) protein -a key regulatory component in steroid biosynthesis-, active ERK1/2 and PKA. Our results indicate that there is an interaction between mitochondrial StAR and ERK1/2, involving a D domain with sequential basic-hydrophobic motifs similar to ERK substrates. As a result of this binding and only in the presence of cholesterol, ERK1/2 phosphorylates StAR at Ser(232). Directed mutagenesis of Ser(232) to a non-phosphorylable amino acid such as Ala (StAR S232A) inhibited in vitro StAR phosphorylation by active ERK1/2. Transient transfection of MA-10 cells with StAR S232A markedly reduced the yield of progesterone production. In summary, here we show that StAR is a novel substrate of ERK1/2, and that mitochondrial ERK1/2 is part of a multimeric protein kinase complex that regulates cholesterol transport. The role of MAPKs in mitochondrial function is underlined.

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  • StAR is a direct target of hormonally stimulated cellular kinase signaling pathways, including the PKA and ERK kinase pathways.

    “Moreover, a number of studies have demonstrated that StAR is a direct target of hormonally stimulated cellular kinase signaling pathways, including the protein kinase A (PKA) and ERK kinase pathways (94, 135, 136).”

    From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [94]

  • Functional partners of the transduceosome include mitochondria-associated members of the 14-3-3 adaptor protein family and kinase signalers such as ERK1/2.

    “In addition, functional partners of the transduceosome have been identified, including mitochondria-associated members of the 14-3-3 adaptor protein family (92, 93) as well as kinase signalers such as extracellular signal-regulated kinase (ERK) 1/2 (94);”

    From Adrenal Mitochondria and Steroidogenesis: From Individual Proteins to Functional Protein Assemblies (2016) · cites this paper as [94]

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References 67 · Cited by 115

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Authors
Poderoso, C., Converso, D. P., Maloberti, P., Duarte, A., Neuman, I., Galli, S., Maciel, F. C., Paz, C., Carreras, M. C., Poderoso, J. J., & Podestá, E. J.
Affiliations
Universidad de Buenos Aires (AR)
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2008-01-16
Volume
3
Issue
1
Pages
e1443
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0001443
PMC
PMC2175533
OpenAlex
W2125244516
Cited by
115
References
67
Citations by year
2026: 2 · 2025: 3 · 2024: 3 · 2022: 4 · 2021: 7 · 2020: 3 · 2019: 1 · 2018: 7 · 2017: 6 · 2016: 9 · 2015: 7 · 2014: 5 · 2013: 10 · 2012: 8
FWCI
5.49
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Greater South Information System
Funders
  • Consejo Nacional de Investigaciones Científicas y Técnicas
  • Universidad de Buenos Aires (CONICET)
  • Agencia Nacional de Promoción Científica y Tecnológica (CONICET)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Keywords
ERK1/2, steroidogenesis, steroidogenic acute regulatory protein, MEK1/2, protein kinase A, MAPK signaling, cholesterol transport, progesterone secretion, Leydig cells, MA-10 cells, epidermal growth factor
MeSH terms
Steroidogenic Acute Regulatory Protein, Cyclic AMP, Animals, Cell Line, Cholesterol, Enzyme Activation, Epidermal Growth Factor, Mitochondria, Phosphoproteins, Phosphorylation, Progesterone, Cyclic AMP-Dependent Protein Kinases, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mice

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