Src Tyrosine Kinase-Induced Loss of Luteinizing Hormone Responsiveness Is via a Ras-Dependent, Phosphatidylinositol-3-Kinase Independent Pathway1

Taylor, C.

doi:10.1095/biolreprod.101.000976

Cited by 10 publications

(10 citation statements)

References 34 publications

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“…Cellular stress leading to the activation of the p38 MAP kinase also induces PKB activation, indicating a multiplicity of signaling pathways that activate PKB. However, Taylor (2002) failed to show an involvement of PI3K in the hormone‐induced steroid formation by MA‐10 cells. In preliminary studies, we also failed to show a role of PKB in Leydig cell steroidogenesis after silencing the PKB mRNA (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Gene and Protein Profiling of the Response of MA‐10 Leydig Tumor Cells to Human Chorionic Gonadotropin

Amri

Huang

et al. 2004

Journal of Andrology

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Activation of the steroidogenic machinery by peptide hormones involves a number of steps for transmitting signals from the plasma membrane to mitochondria in a spatially and temporally coordinated manner. Although key proteins mediating the hormonal signal have been identified, recent data suggest that the pathway might involve more complex protein-protein and protein-lipid interactions. Genomic and proteomic methods of analysis, namely the Affymetrix Murine Genome U74A v2 GeneChip and the BD PowerBlot Western Array, were used to identify human chorionic gonadotropin (hCG)-induced changes in mRNA and protein of MA-10 Leydig tumor cells that parallel the increase seen in progesterone synthesis. To analyze the massive amount of data that was generated, a comprehensive protein information matrix summarizing the features of each gene or protein, including its known properties, as well as annotations derived by homology-based functional inference, was developed. Of the genes examined by Affymetrix array, approximately 79 were differentially expressed and of gene products examined by PowerBlot, 9 were differentially expressed (above twofold). Changes in the expression of selected transcripts of interest were confirmed using real-time quantitative polymerase chain reaction and immunoblot analyses. Collectively, these results indicate that hormonal regulation of steroidogenesis is a complex phenomenon, involving proteins that participate in various known and novel pathways, which are implicated in transmitting signals from the plasma membrane to mitochondria and nucleus.

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Section: Discussionmentioning

confidence: 99%

Gene and Protein Profiling of the Response of MA‐10 Leydig Tumor Cells to Human Chorionic Gonadotropin

Amri

Huang

et al. 2004

Journal of Andrology

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“…Activation of ERK cascade may involve other signaling molecules such as SFKs, β-arrestins, PKA, Ras, Shc and the EGFR as intermediates in the pathway [64-69]. Studies carried out employing inhibitors and dominant negative constructs of SFKs have shown that many of these molecules interact with the canonical LH/CGR activated signaling pathway resulting in altered responsiveness to steroidogenesis in ovarian cells [19,70,71], MA-10 tumor Leydig cells [18,72,73] and adrenal cells [74,75]. In the present study, expression of genes belonging to SFKs confirm low levels of activated Src during high steroidogenic state or increased activated levels of Src during low steroidogenic state of the CL.…”

Section: Discussionmentioning

confidence: 99%

“…The interaction between the LH/CGR and SFKs can possibly either be a direct [17,76] or indirect involving Pyk2 [77] or β-arrestins [66,78] to keep Src activation in check. Thus, increased Src activation observed during low P 4 secretion may be due to reduced responsiveness to LH since cAMP-PDE activity involving Ras activation may be affected as observed in MA-10 and ovarian theca cells [18,19,73]. The role of PDE in the regulation of endocrine cell functions has been well documented [79-83].…”

Section: Discussionmentioning

confidence: 99%

Involvement of Src family of kinases and cAMP phosphodiesterase in the luteinizing hormone/chorionic gonadotropin receptor-mediated signaling in the corpus luteum of monkey

Kunal

Asaithambi

Medhamurthy

2012

Reprod Biol Endocrinol

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BackgroundIn higher primates, during non-pregnant cycles, it is indisputable that circulating LH is essential for maintenance of corpus luteum (CL) function. On the other hand, during pregnancy, CL function gets rescued by the LH analogue, chorionic gonadotropin (CG). The molecular mechanisms involved in the control of luteal function during spontaneous luteolysis and rescue processes are not completely understood. Emerging evidence suggests that LH/CGR activation triggers proliferation and transformation of target cells by various signaling molecules as evident from studies demonstrating participation of Src family of tyrosine kinases (SFKs) and MAP kinases in hCG-mediated actions in Leydig cells. Since circulating LH concentration does not vary during luteal regression, it was hypothesized that decreased responsiveness of luteal cells to LH might occur due to changes in LH/CGR expression dynamics, modulation of SFKs or interference with steroid biosynthesis.MethodsSince, maintenance of structure and function of CL is dependent on the presence of functional LH/CGR its expression dynamics as well as mRNA and protein expressions of SFKs were determined throughout the luteal phase. Employing well characterized luteolysis and CL rescue animal models, activities of SFKs, cAMP phosphodiesterase (cAMP-PDE) and expression of SR-B1 (a membrane receptor associated with trafficking of cholesterol ester) were examined. Also, studies were carried out to investigate the mechanisms responsible for decline in progesterone biosynthesis in CL during the latter part of the non-pregnant cycle.Results and discussionThe decreased responsiveness of CL to LH during late luteal phase could not be accounted for by changes in LH/CGR mRNA levels, its transcript variants or protein. Results obtained employing model systems depicting different functional states of CL revealed increased activity of SFKs [pSrc (Y-416)] and PDE as well as decreased expression of SR-B1correlating with initiation of spontaneous luteolysis. However, CG, by virtue of its heroic efforts, perhaps by inhibition of SFKs and PDE activation, prevents CL from undergoing regression during pregnancy.ConclusionsThe results indicated participation of activated Src and increased activity of cAMP-PDE in the control of luteal function in vivo. That the exogenous hCG treatment caused decreased activation of Src and cAMP-PDE activity with increased circulating progesterone might explain the transient CL rescue that occurs during early pregnancy.

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“…Further studies demonstrated that stimulation of Src activity resulted in reduced steroidogenesis. In porcine thecal cells PDGF-mediated stimulation of Src activity resulted in reduced gonadotropin-stimulated steroidogenesis [36]. In addition, transfection of MA10 and TM3 Leydig cell lines with a temperature sensitive constitutively active Src mutant also resulted in inhibition of cAMP-stimulated steroidogenesis [6, 8].…”

Section: Discussionmentioning

confidence: 99%

The Src tyrosine kinase pathway regulates thecal CYP17 expression and androstenedione secretion

et al. 2008

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In order to evaluate the role of Src tyrosine kinase in thecal cell steroidogenesis, a pharmacological approach was utilized by treating enriched populations of mouse ovarian theca-interstitial cells in vitro with a direct Src kinase inhibitor, PP2. Inhibition of Src with PP2 increased both basal and forskolin-stimulated androstenedione secretion, and increased cytochrome P450 17-alpha hydroxylase-lyase (CYP17) promoter activity and steady state mRNA. PP2 did not change thecal levels of StAR mRNA. Inhibition of mitogen-activated protein kinase kinase, a downstream regulator of Src activity, using PD98059 also increased forskolin-stimulated secretion of androstenedione above forskolin alone, but had no effect on basal secretion of androstenedione. Src inhibition increased mitogen-activated protein kinase phosphatase-1 protein and decreased phosphorylation of SF-1, which correlated with increased CYP17 promoter activity and mRNA levels. These results implicate Src tyrosine kinase in the regulation of CYP17 and thecal androgen secretion.

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Src Tyrosine Kinase-Induced Loss of Luteinizing Hormone Responsiveness Is via a Ras-Dependent, Phosphatidylinositol-3-Kinase Independent Pathway1

Cited by 10 publications

References 34 publications

Gene and Protein Profiling of the Response of MA‐10 Leydig Tumor Cells to Human Chorionic Gonadotropin

Gene and Protein Profiling of the Response of MA‐10 Leydig Tumor Cells to Human Chorionic Gonadotropin

Involvement of Src family of kinases and cAMP phosphodiesterase in the luteinizing hormone/chorionic gonadotropin receptor-mediated signaling in the corpus luteum of monkey

The Src tyrosine kinase pathway regulates thecal CYP17 expression and androstenedione secretion

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