Crosstalk (biology) - Crosstalk Between Signaling Pathways

Crosstalk Between Signaling Pathways

One example of crosstalk between proteins in a signaling pathway can be seen with cyclic adenosine monophosphate's (cAMP) role in regulating cell proliferation by interacting with the mitogen-activated protein (MAP) kinase pathway. cAMP is a compound synthesized in cells by adenylate cyclase in response to a variety of extracellular signals. cAMP primarily acts as an intracellular second messenger whose major intracellular receptor is the cAMP-dependent protein kinase (PKA) that acts through the phosphorylation of target proteins. The signal transduction pathway begins with ligand-receptor interactions extracellularly. This signal is then transduced through the membrane, stimulating adenylyl cyclase on the inner membrane surface to catalyze the conversion of ATP to cAMP.

ERK, a participating protein in the MAPK signaling pathway, can be activated or inhibited by cAMP. cAMP can inhibit ERKs in a variety of ways, most of which involve the cAMP-dependent protein kinase (PKA) and the inhibition of Ras-dependent signals to Raf-1. However, cAMP can also stimulate cell proliferation by stimulating ERKs. This occurs through the induction of specific genes via phosphorylation of the transcription factor CREB by PKA. Though ERKs do not appear to be a requirement for this phosphorylation of CREB, the MAPK pathway does play into crosstalk again, as ERKs are required to phosphorylate proteins downstream of CREB. Other known examples of the requirement of ERKs for cAMP-induced transcriptional effects include induction of the prolactin gene in pituitary cells, and of the dopamine beta-hydroxylate gene in pheochromocytomal cells (PC12). A number of diverse mechanisms exist by which cAMP can influence ERK signaling. Most mechanisms involving cAMP inhibition of ERKs uncouple Raf-1 from Ras activation through direct interaction of PKA with Raf-1 or indirectly through PKA interaction with the GTPase Rap1 (See Figure 1). PKA may also negatively regulate ERKs by the activation of PTPases. Mechanisms for the activation of ERKs by cAMP are even more varied, usually including Rap1 or Ras, and even cAMP directly.