21.6:
Interactions Between Signaling Pathways
Signaling molecules and receptors work in different combinations to regulate the diverse cellular functions.
Signals from different receptors, each stimulated by their ligand, can converge to activate a common downstream effector — a protein that triggers a specific cellular response.
Individual signals from G-protein coupled receptors, tyrosine kinase receptors, or integrins, can activate Raf, a Ras effector and trigger the mitogen-activated protein or MAP kinase pathway.
Signals from an activated receptor can also diverge to activate multiple downstream pathways. For example, insulin binding to its receptor can trigger both phosphoinositide 3 kinase and Ras pathways.
Pathways cross-talk when molecules of one pathway are either shared between multiple pathways or molecules of one pathway are modified by enzymes of another.
In the cyclic AMP pathway protein kinase A, PKA activates the transcription factor, cyclic AMP response element-binding protein by phosphorylation. Additionally, through crosstalk, PKA can also block the signal transduction through the MAP kinase pathway.
21.6:
Interactions Between Signaling Pathways
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response observed when either pathway is individually activated.
Similarly, pathways diverge when an upstream signaling component interacts with multiple downstream components. For example, the action of a neurotransmitter on a target cell can cause distinct effects to appear together. Together, convergence and divergence create networks of cross-interaction where relatively simple signals elicit complex responses, provide functional flexibility, and preserve signal specificity.
The growth inhibitory effect of the tumor suppressor protein, p53, is due to its interaction with multiple signaling pathways. Depending on the stimulus, it is activated when phosphorylated by one of the several protein kinases. The activated p53 can act as a transcription factor to induce or suppress genes from different signaling pathways.
MAP kinases phosphorylate and activate p53 in response to the signal, which causes cell cycle arrest and apoptosis as well as other p53-mediated cellular responses. p53 can also negatively regulate MAP kinase signaling via the transcriptional activation of phosphatases that inhibit MAP kinases. It is interesting to note that alteration of both p53 and MAPK signaling pathways is observed in a majority of human cancers causing dysregulated cell proliferation.