Trends in Cell Biology
Volume 12, Issue 6, 1 June 2002, Pages 258-266
Journal home page for Trends in Cell Biology

Review
Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation

https://doi.org/10.1016/S0962-8924(02)02294-8Get rights and content

Abstract

Hormonal stimulation of cyclic adenosine monophosphate (cAMP) and the cAMP-dependent protein kinase PKA regulates cell growth by multiple mechanisms. A hallmark of cAMP is its ability to stimulate cell growth in many cell types while inhibiting cell growth in others. In this review, the cell type-specific effects of cAMP on the mitogen-activated protein (MAP) kinase (also called extracellular signal-regulated kinase, or ERK) cascade and cell proliferation are examined. Two basic themes are discussed. First, the capacity of cAMP for either positive or negative regulation of the ERK cascade accounts for many of the cell type-specific actions of cAMP on cell proliferation. Second, there are several specific mechanisms involved in the inhibition or activation of ERKs by cAMP. Emerging new data suggest that one of these mechanisms might involve the activation of the GTPase Rap1, which can activate or inhibit ERK signaling in a cell-specific manner.

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,

References (125)

  • A. Feliciello

    The localization and activity of cAMP-dependent protein kinase affect cell cycle progression in thyroid cells

    J. Biol. Chem.

    (2000)
  • M. Kubicek

    Dephosphorylation of Ser-259 regulates Raf-1 membrane association

    J. Biol. Chem.

    (2002)
  • M.F. Sidovar

    Phosphorylation of serine 43 is not required for inhibition of C-Raf kinase by the cAMP-dependent protein kinase

    J. Biol. Chem.

    (2000)
  • H. Kitayama

    A ras-related gene with transformation suppressor activity

    Cell

    (1989)
  • D.L. Altschuler

    Cyclic AMP-dependent activation of Rap1b

    J. Biol. Chem.

    (1995)
  • W. Qiu

    Cell type-specific regulation of B-Raf kinase by cAMP and 14-3-3 proteins

    J. Biol. Chem.

    (2000)
  • P. Zanassi

    cAMP-dependent protein kinase induces cAMP-response element-binding protein phosphorylation via an intracellular calcium release/ERK-dependent pathway in striatal neurons

    J. Biol. Chem.

    (2001)
  • M. Vossler

    cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway

    Cell

    (1997)
  • L.L. Dugan

    Differential effects of cAMP in neurons and astrocytes. Role of B-raf

    J. Biol. Chem.

    (1999)
  • J.M. Schmitt et al.

    β2-adrenergic receptor activates extracellular regulated kinases (ERKs) via the small G protein Rap1 and the serine/threonine kinase B-Raf

    J. Biol. Chem.

    (2000)
  • J.M. Schmitt et al.

    PKA phosphorylation of Src mediates cAMP's inhibition of cell growth via Rap1

    Mol. Cell

    (2002)
  • F.J. Zwartkruis et al.

    Ras and Rap1: two highly related small GTPases with distinct function

    Exp. Cell Res.

    (1999)
  • L. Wang

    Cyclic AMP inhibits extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/Akt pathways by inhibiting Rap1

    J. Biol. Chem.

    (2001)
  • E. Caron

    The GTPase Rap1 controls functional activation of macrophage integrin alphaMbeta2 by LPS and other inflammatory mediators

    Curr. Biol.

    (2000)
  • A. Arai

    Rap1 is activated by erythropoietin or interleukin-3 and is involved in regulation of beta 1 integrin-mediated hematopoietic cell adhesion

    J. Biol. Chem.

    (2001)
  • N. Tsukamoto

    Rap1 GTPase-activating protein SPA-1 negatively regulates cell adhesion

    J. Biol. Chem.

    (1999)
  • L. Barberis

    Distinct roles of the adaptor protein shc and focal adhesion kinase in integrin signaling to ERK

    J. Biol. Chem.

    (2000)
  • S. Kim

    Cyclic AMP inhibits Akt activity by blocking the membrane localization of PDK1

    J. Biol. Chem.

    (2001)
  • B.H. Zhang

    Serum- and glucocorticoid-inducible kinase SGK phosphorylates and negatively regulates B-Raf

    J. Biol. Chem.

    (2001)
  • A. Misra-Press

    A novel mitogen-activated protein kinase phosphatase: structure, expression and regulation

    J. Biol. Chem.

    (1995)
  • C. Burgun

    Cyclic AMP-elevating agents induce the expression of MAP kinase phosphatase-1 in PC12 cells

    FEBS Lett.

    (2000)
  • R. Plevin

    Cyclic AMP inhibitors inhibits PDGF-stimulated mitogen-activated protein kinase activity in rat aortic smooth muscle cells via inactivation of c-Raf-1 kinase and induction of MAP kinase phosphatase-1

    Cell. Signal.

    (1997)
  • C. Wellbrock

    Activation of p59Fyn leads to melanocyte dedifferentiation by influencing MKP-1-regulated mitogen-activated protein kinase signaling

    J. Biol. Chem.

    (2002)
  • T. Mutoh

    Differential signaling cascade of MAP kinase and S6 kinase depends on 3′,5′-monophosphate concentration in Schwann cells: correlation to cellular differentiation and proliferation

    Brain Res.

    (1998)
  • D.M. Vogt Weisenhorn

    Coupling of cAMP/PKA and MAPK signaling in neuronal cells is dependent on developmental stage

    Exp. Neurol.

    (2001)
  • S.S. Grewal

    Calcium and cAMP signals differentially regulate cAMP-responsive element-binding protein function via a Rap1-extracellular signal-regulated kinase pathway

    J. Biol. Chem.

    (2000)
  • S.S. Grewal

    Extracellular-signal-regulated kinase signalling in neurons

    Curr. Opin. Neurobiol.

    (1999)
  • S.L. Patterson

    Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase

    Neuron

    (2001)
  • D.J. Swanson

    AP1 proteins mediate the cAMP response of the dopamine beta-hydroxylase gene

    J. Biol. Chem.

    (1998)
  • M.H. Verheijen et al.

    Parathyroid hormone activates mitogen-activated protein kinase via a cAMP-mediated pathway independent of Ras

    J. Biol. Chem.

    (1997)
  • J.V. Barnier

    The mouse B-raf gene encodes multiple protein isoforms with tissue-specific expression

    J. Biol. Chem.

    (1995)
  • S. Kao

    Identification of the mechanisms regulating the differential activation of the MAPK cascade by epidermal growth factor and nerve growth factor in PC12 cells

    J. Biol. Chem.

    (2001)
  • M.C. MacNicol et al.

    Nerve growth factor-stimulated B-Raf catalytic activity is refractory to inhibition by cAMP-dependent protein kinase

    J. Biol. Chem.

    (1999)
  • J.M. Lindquist

    β3- and α1-adrenergic Erk1/2 activation is Src- but not Gi-mediated in brown adipocytes

    J. Biol. Chem.

    (2000)
  • S. Dremier

    Activation of the small G protein Rap1 in dog thyroid cells by both cAMP-dependent and -independent pathways

    Biochem. Biophys. Res. Commun.

    (2000)
  • F.C. Mei

    Differential signaling of cyclic AMP. Opposing effects of exchange protein directly activated by cAMP and cAMP-dependent protein kinase A on protein kinase B activation

    J. Biol. Chem.

    (2002)
  • M.M. Gottesman et al.

    The role of cAMP in regulating tumour cell growth

    Cancer Surv.

    (1986)
  • J.S. Richards

    New signaling pathways for hormones and cyclic adenosine 3′,5′-monophosphate action in endocrine cells

    Mol. Endocrinol.

    (2001)
  • M. Mikula

    Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene

    EMBO J.

    (2001)
  • R. Cospedal

    Differential regulation of extracellular signal-regulated protein kinases (ERKs) 1 and 2 by cAMP and dissociation of ERK inhibition from anti-mitogenic effects in rabbit vascular smooth muscle cells

    Biochem. J.

    (1999)
  • Cited by (772)

    View all citing articles on Scopus
    View full text