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A Pipeline to Investigate the Structures and Signaling Pathways of Sphingosine 1-Phosphate Receptors
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PAM mediates sustained inhibition of cAMP signaling by sphingosine-1-phosphate

Sandra C Pierre1, Julia Häusler, Kerstin Birod

  • 1Pharmazentrum frankfurt, Klinikum der Johann Wolfgang Goethe-Universität Frankfurt, Frankfurt, Germany.

The EMBO Journal
|July 17, 2004
PubMed

Insights

Protein Associated with Myc (PAM) inhibits adenylyl cyclase. Sphingosine-1-phosphate (S1P) recruits PAM to the plasma membrane, causing long-lasting inhibition of cyclic AMP (cAMP) signaling.

Area of Science:

  • Cellular signaling
  • Molecular biology
  • Biochemistry

Background:

  • Protein Associated with Myc (PAM) is a potent inhibitor of adenylyl cyclase.
  • Understanding PAM's regulation is crucial for deciphering cyclic AMP (cAMP) signaling pathways.

Purpose of the Study:

  • To investigate the cellular localization and regulation of PAM.
  • To identify the serum factor responsible for PAM translocation and its effect on adenylyl cyclase activity.

Main Methods:

  • Cellular localization studies in HeLa cells.
  • Purification and identification of serum factors.
  • Measurement of adenylyl cyclase activity and cAMP signaling in response to sphingosine-1-phosphate (S1P).

Main Results:

  • PAM is localized to the endoplasmic reticulum and translocates to the plasma membrane upon serum treatment.
  • Sphingosine-1-phosphate (S1P) was identified as the serum factor inducing PAM translocation.
  • S1P triggers a biphasic adenylyl cyclase inhibition, with a late, PAM-dependent phase impacting cAMP signaling for up to 240 minutes.

Conclusions:

  • PAM acts as a long-lasting, non-transcriptional regulator of adenylyl cyclase activity.
  • PAM-S1P interaction provides a novel mechanism for the temporal control of cAMP signaling.

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