Trends in Cell Biology
ReviewCrosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation
Section snippets
The inhibition of cell proliferation by cAMP
It has long been appreciated that cAMP can inhibit cell growth by blocking growth factor activation of ERKs. The antiproliferative actions of hormones, cAMP and PKA have been linked to inhibition of the ERK kinase cascade in many cell types. Examples are provided in Table 1.
Hormones increase intracellular cAMP levels through G-protein-coupled receptors (GPCRs) that link hormones to the heterotrimeric G protein Gαs. Constitutively activated mutants of Gαs can block Ras-dependent proliferation of
Regulation of Rap1 and ERKs by PKA activation of Src kinase
The activation of Rap1 by PKA has been demonstrated in a wide variety of cells [39], including neurons 40., 41., glia [42] and fibroblasts 37., 43.. Although Rap1 can be phosphorylated directly by PKA [44], this phosphorylation step is not required for the activation of Rap1 by cAMP [36]. It is possible that phosphorylation of Rap1 by PKA plays a role in influencing effector pathways of Rap1 that are distinct from Raf-1, as suggested by Altschuler and coworkers who have recently identified a
Rap1 activation of B-Raf
Rap1 has another action in certain cell types – it can activate the Raf isoform B-Raf. This action is independent of Ras and provides a pathway for cAMP to activate ERKs. Early studies in PC12 cells determined that the target of the activation of ERKs by cAMP was upstream of MEK [22]. The Ras independence of the effects of cAMP was suggested by studies examining the regulation of ERKs by parathyroid hormone and cAMP in Chinese hamster ovary cells [80] and by forskolin in PC12 cells [41]. A role
Concluding remarks
Numerous distinct mechanisms exist that allow cAMP to regulate ERK signaling. It will be critical to determine whether any specific mechanism has broad applicability to a variety of cell types or is limited to selected cells and stimuli. Most mechanisms explaining cAMP inhibition of ERKs involve the uncoupling of Raf-1 from Ras activation, either by direct actions of PKA on Raf-1 or through the actions of PKA on the GTPase Rap1. Other mechanisms, including the activation of selected PTPases,
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