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Related Experiment Videos

cAMP signaling selectively influences Ras effectors pathways.

I Ciullo1, G Diez-Roux, M Di Domenico

  • 1Dipartimento di Biologia e Patologia Molecolare e Cellulare, Centro di Endocrinologia ed Oncologia Sperimentale del C.N.R., Facoltà di Medicina, Università "Federico II" via S.Pansini 5, Napoli, Italy.

Oncogene
|April 21, 2001
PubMed
Summary
This summary is machine-generated.

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Thyrotropin (TSH) signaling activates cyclic AMP (cAMP) and protein kinase A (PKA), which promotes thyroid cell growth by activating phosphatidylinositol 3-kinase (PI3K) signaling over Raf-1-ERK pathways.

Area of Science:

  • Cellular Biology
  • Molecular Signaling
  • Endocrinology

Background:

  • Thyrotropin (TSH) stimulates thyroid cell survival and growth through a G protein-coupled receptor, increasing cyclic AMP (cAMP) and activating protein kinase A (PKA).
  • p21 Ras is known to be essential for TSH-induced mitogenesis, but the precise molecular mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanism by which TSH signaling, specifically involving Ras p21, regulates thyroid cell proliferation.
  • To identify the downstream effectors of Ras p21 in TSH-induced signaling pathways.

Main Methods:

  • Investigated the role of Ras p21 activity in the G0-G1 transition of the cell cycle following TSH stimulation.
  • Utilized phosphatidylinositol 3-kinase (PI3K) inhibitors to assess their impact on TSH-induced DNA synthesis.

Related Experiment Videos

  • Examined the formation of protein complexes, including PI3K-p21 Ras and Ras-Raf1, under various signaling conditions.
  • Analyzed the effect of PKA phosphorylation on p85 subunit of PI3K and its interaction with Ras.

    • Main Results:

    • Ras p21 activity is crucial for the G0-G1 transition in TSH-induced cell cycle progression.
    • The p85-p110 PI3K is identified as a key downstream effector of Ras p21 in TSH signaling.
    • PI3K inhibitors effectively block TSH-induced DNA synthesis.
    • cAMP-PKA signaling promotes the formation of PI3K-p21 Ras complexes while reducing Ras-Raf1 complexes.
    • PKA directly phosphorylates the p85 subunit of PI3K, enhancing PI3K-Ras interaction and stabilizing the PI3K complex.
    • cAMP signaling inhibits Raf-1-ERK signaling by reducing Raf1 availability to Ras, thereby favoring PI3K signaling.

    Conclusions:

    • TSH-induced proliferation is mediated by PI3K signaling, which is selectively activated over Raf-1-ERK pathways.
    • PKA-mediated phosphorylation of PI3K's p85 subunit plays a critical role in stabilizing the PI3K-Ras complex, enhancing downstream signaling.
    • This study reveals a novel mechanism by which cAMP signaling selectively modulates Ras effector pathways to control cell proliferation.