Cross-talk between calcium and protein kinase A in the regulation of cell migration

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Calcium (Ca2+) and the cAMP-dependent protein kinase (PKA) are pleiotropic cellular regulators and both exert powerful, diverse effects on cytoskeletal dynamics, cell adhesion, and cell migration. Localization, by A-kinase-anchoring proteins (AKAPs), of PKA activity to the protrusive leading edge, integrins, and other regulators of cytoskeletal dynamics has emerged as an important facet of its role in cell migration. Additional recent work has firmly established the importance of Ca2+ influx through mechanosensitive transient receptor potential (TRP) channels and through store-operated Ca2+ entry (SOCE) in cell migration. Finally, there is considerable evidence showing that these mechanisms of Ca2+ influx and PKA regulation intersect  and often interact  and thus may work in concert to translate complex extracellular cues into the intracellular biochemical anisotropy required for directional cell migration.

Highlights

► Ca2+ and PKA are pleiotropic cellular regulators of cell migration. ► There are numerous mechanisms through which Ca2+ and PKA can regulate each other. ► TRP channels and store-operated Ca2+ entry are newly and strongly implicated in migration. ► We present published and new, unpublished data connecting PKA to TRP channels and SOCE. ► We hypothesize that Ca2+/PKA cross-talk is an important regulatory axis for migration.

Introduction

Successful cell migration requires cells to interpret their extracellular environment through diverse receptors in order to regulate and rearrange distinct cytoskeletal and adhesive events in subcellular space. Thus, the cell migration machinery must be regulated by signaling intermediates that can be activated by diverse stimuli and can exert control over a large number of downstream targets  all with temporal and spatial specificity. In this regard, two systems  Ca2+ influx and signaling through the cAMP-dependent protein kinase (PKA)  are perfectly suited [1, 2, 3]. However, despite intense study of Ca2+ and PKA, and despite  or perhaps because of  their myriad possible connections to cell migration, our understanding of how these signals control cell motility is far from complete.

Some of the first formal descriptions of Ca2+ patterns in migrating cells established the enduring tenet that [Ca2+]i during migration is highly variable in both time and subcellular space (e.g. [4, 5]). Since then, the mechanisms controlling this variability have been a major research focus. Recent work has highlighted the importance of Ca2+ influx from two distinct sources  namely, mechanosensitive channels and store-operated Ca2+ entry (SOCE)  in the regulation of migration.

Over a similar period, the role of PKA as both a positive and negative regulator of cell motility was established in a number of systems [3]. A critical advance in understanding this regulation came from incorporating the importance of AKAP-mediated localization in specifying the effects of PKA [6] and demonstrating that PKA is spatially regulated in motile cells [7••], providing a mechanism through which its promiscuous activity can be brought to bear specifically on processes in migration. Recent work has confirmed and expanded this observation, bringing specific migration-associated or cytoskeleton-associated AKAPs to the fore and providing mechanisms for focusing PKA activity even more tightly on discrete cytoskeletal events.

Finally, a wealth of literature demonstrates the substantial cross-talk and coincidence between Ca2+ and cAMP/PKA [8•, 9, 10, 11••], and recent observations further support the hypothesis that these pathways may act in concert to achieve the specificity and diversity of controls required for the regulation of cell migration.

Section snippets

Ca2+ in migration I  it's a stretch, but there are flickers of hope

Recent work investigating Ca2+ in migration has capitalized on our growing understanding of the importance of mechanical forces in cell migration [12] by demonstrating important roles for mechanosensitive stretch-activated Ca2+ channels (SACCs) during migration. Motile cells generate a number of cellular forces [12] which inevitably impinge on the shape and tension of the plasma membrane. Given that nearly every type of cell expresses some form of mechanosensitive or stretch-activated ion

Ca2+ in migration II  what's in store?

As mentioned above, TRPM7-mediated flickers do not act alone, but rather occur on the backdrop of a diffuse gradient of Ca2+ that increases from the front to the rear of the cell [23••]. Also, while flicker activity was completely eliminated by RNAi against TRPM7, flicker amplitude (but not probability) was also partially blunted by inhibition of the function or expression of the inositol (3,4,5) trisphosphate receptor (IP3R) [23••]. This suggests that Ca2+ flickers are locally triggered by

Whither goest the Ca2+ in migration?

Currently, it is unknown whether Stim1/Orai1/SOCE exert a global or localized effect in migrating cells. In that regard, an intriguing hypothesis is that, in a cell undergoing chemotaxis, the higher relative concentration of extracellular stimulus at the leading edge would produce a localized or graded concentration of intracellular IP3, which would in turn elicit localized store depletion and SOCE within the leading edge. This would result in the generation of leading edge Ca2+ signals with

PKA in cell migration  still in the lead

PKA has numerous cytoskeleton-associated and migration-associated targets [3]  indeed, various subunits of PKA have recently been identified as part of a myosin II-responsive focal adhesion proteome [41], placing PKA in immediate proximity to many known and potential targets. Given this, and the fact that PKA can exert both negative and positive effects on cell migration [7••], it is not surprising that the role of PKA in migration is critically dependent on its localization through AKAPs. In

Ca2+ and cAMP/PKA: connections

The collaboration between Ca2+ and cAMP/PKA signaling in regulating cell function has been appreciated for decades [8] and has since been expertly reviewed [9, 10, 11••]. Indeed, there are numerous, elegant examples of how closely connected the two signals can be in both time and space (e.g. [53]; reviewed in [11••]). The number of levels at which Ca2+ and PKA can regulate one another, combined with the strong influence each signal has over migration-associated processes, makes it quite likely

Conclusions

Beyond the Ca2+ events discussed above, it should be noted that PKA interacts with numerous other factors that control or interpret Ca2+ flux and that have been implicated in cell migration [10, 66, 67]. The hypothesis  or perhaps ‘prediction’  being proffered here is that, based on the strong influence of Ca2+ and PKA on cell migration and the staggering complexity and ubiquity of cross-talk between these signals, collaboration between Ca2+ and PKA will play a fundamentally important role in the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The author would like to thank Drs. Richard Lewis (Stanford University) and David Clapham (Harvard University) for Orai1 and TRPM7 plasmids, respectively and Andrew McKenzie for helpful discussions. Work in the author's laboratory is supported by grants from the NIH (GM074204) and the Lake Champlain Cancer Research Organization.

References (67)

  • O. Krylyshkina et al.

    Nanometer targeting of microtubules to focal adhesions

    J Cell Biol

    (2003)
  • C.J. Lim et al.

    Integrin-mediated protein kinase A activation at the leading edge of migrating cells

    Mol Biol Cell

    (2008)
  • H. Jin et al.

    A PKA-Csk-pp60Src signaling pathway regulates the switch between endothelial cell invasion and cell–cell adhesion during vascular sprouting

    Blood

    (2010)
  • Y. Obara et al.

    PKA phosphorylation of Src mediates Rap1 activation in NGF and cAMP signaling in PC12 cells

    J Cell Sci

    (2004)
  • J. Hanoune et al.

    Regulation and role of adenylyl cyclase isoforms

    Annu Rev Pharmacol Toxicol

    (2001)
  • D.T. Brandt et al.

    Get to grips: steering local actin dynamics with IQGAPs

    EMBO Rep

    (2007)
  • H.C. Fan et al.

    Activation of the TRPV4 ion channel is enhanced by phosphorylation

    J Biol Chem

    (2009)
  • M.J. Berridge et al.

    The versatility and universality of calcium signalling

    Nat Rev Mol Cell Biol

    (2000)
  • G. Pidoux et al.

    Specificity and spatial dynamics of protein kinase A signaling organized by A-kinase-anchoring proteins

    J Mol Endocrinol

    (2010)
  • P.W. Marks et al.

    Transient increases in cytosolic free calcium appear to be required for the migration of adherent human neutrophils

    J Cell Biol

    (1990)
  • R.A. Brundage et al.

    Calcium gradients underlying polarization and chemotaxis of eosinophils

    Science

    (1991)
  • A.K. Howe et al.

    Spatial regulation of the cAMP-dependent protein kinase during chemotactic cell migration

    Proc Natl Acad Sci U S A

    (2005)
  • M.J. Berridge

    The interaction of cyclic nucleotides and calcium in the control of cellular activity

    Adv Cyclic Nucleotide Res

    (1975)
  • A.E. Bugrim

    Regulation of Ca2+ release by cAMP-dependent protein kinase. A mechanism for agonist-specific calcium signaling?

    Cell Calcium

    (1999)
  • J.I. Bruce et al.

    Crosstalk between cAMP and Ca2+ signaling in non-excitable cells

    Cell Calcium

    (2003)
  • J. Arnadottir et al.

    Eukaryotic mechanosensitive channels

    Annu Rev Biophys

    (2010)
  • T. Kobayashi et al.

    Sensing substrate rigidity by mechanosensitive ion channels with stress fibers and focal adhesions

    Curr Opin Cell Biol

    (2010)
  • J. Lee et al.

    Regulation of cell movement is mediated by stretch-activated calcium channels

    Nature

    (1999)
  • S. Munevar et al.

    Regulation of mechanical interactions between fibroblasts and the substratum by stretch-activated Ca2+ entry

    J Cell Sci

    (2004)
  • L.T. Su et al.

    TRPM7 regulates cell adhesion by controlling the calcium-dependent protease calpain

    J Biol Chem

    (2006)
  • R. Ramadass et al.

    Spectrally and spatially resolved fluorescence lifetime imaging in living cells: TRPV4-microfilament interactions

    Arch Biochem Biophys

    (2007)
  • J. Waning et al.

    A novel function of capsaicin-sensitive TRPV1 channels: involvement in cell migration

    Cell Calcium

    (2007)
  • A. Fabian et al.

    TRPC1 channels regulate directionality of migrating cells

    Pflugers Arch

    (2008)
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