TABLE 1

Overview of modifications and interactions that influence PDE4 activity and the affinity of PDE4 inhibitors

Effect on PDE4 ActivityInteraction/ModificationEffect on Inhibitor affinityCommentsReferences
IncreaseAktFang et al., 2015
B55α PP2a subunitDephosphorylation at ERK site on PDE4D5Yun et al., 2019a
CalcineurinProtects against degradationZhu et al., 2010
CaMKIIMika et al., 2015
Caspase-3 cleavageHuston et al., 2000
CDK5Possible synergistic activation by PKAPlattner et al., 2015
ERKShort isoforms of PDE4B, 4C, and 4D onlyBaillie et al., 2000; MacKenzie et al., 2000
mAKAP/AKAP6Presumably through mAKAP-sequestered PKACarlisle Michel et al., 2004; Dodge et al., 2001
Metal binding (Mg2+)Increase (R-rolipram, S-rolipram, CDP-840, cilomilast, roflumilast, piclamilast, PMNPQ)Huang et al., 2007; Laliberte et al., 2000; Liu et al., 2001; Saldou et al., 1998
Oxidative stress switch kinaseNo effect (rolipram)Switches ERK inhibition to activation, phosphomimetic mutation prevents dimerizationBolger, 2016; Hill et al., 2006
Phosphatidic acidDimerization necessary for activationGrange et al., 2000; Nemoz et al., 1997; Richter and Conti, 2004
PhosphatidylserineNemoz et al., 1997
PI3KγD'Andrea et al., 2015; Ghigo et al., 2012
PKAIncrease (rolipram, BPN14770, RS-25344, RS-33793)Alvarez et al., 1995; Bolger, 2016; Hoffmann et al., 1998; MacKenzie et al., 2002; Sette and Conti, 1996; Zhang et al., 2018
RACK1Increase (rolipram)Ablates dimerizationBird et al., 2010; Bolger et al., 2006; Bolger et al., 2002; Yarwood et al., 1999
RhebStabilizes PDE4D protein expressionKim et al., 2010; Meng et al., 2017
SIK1Kim et al., 2015; Liu et al., 2020
DecreaseCC2D1APrevents activation by PKAAl-Tawashi and Gehring, 2013
DISC1PKA phosphorylation releases DISC1Cheung et al., 2007; Millar et al., 2005; Murdoch et al., 2007
ERKLong and supershort isoforms of PDE4B, 4C, and 4D onlyBaillie et al., 2000; MacKenzie et al., 2000
PHD2Presumably induces PDE4 protein degradationHuo et al., 2012
PKA (PDE4D7-specific)Byrne et al., 2015
Smurf2Ubiquitination and degradation of PDE4BCai et al., 2018
SUMO E3 ligase PIASyAugments PKA phosphorylation, reduces ERK inhibitionLi et al., 2010
UCR1-UCR2 interactionNo effect (IBMX, rolipram, piclamilast, RS-25344)Beard et al., 2000; Saldou et al., 1998
XAP2/AIPIncrease (rolipram)Bolger et al., 2003
NoneDimerizationIncrease (R-rolipram), no effect (piclamilast)/no effect (rolipram)/increased (rolipram)Dimerization enables UCR2 to bind rolipramBolger et al., 2015; Cedervall et al., 2015; Richter and Conti, 2004
Lyn, SrcIncrease for rolipramBeard et al., 2002; Beard et al., 1999; McPhee et al., 1999; O'Connell et al., 1996
MK2 phosphorylationPhosphomimetic mutation prevents dimerization; attenuation PKA activation and interaction with DISC1 and AIP; enhances interaction of PDE4A4 with p75NTRBolger, 2016; Houslay et al., 2019; MacKenzie et al., 2011
p75NTRHouslay et al., 2019; Sachs et al., 2007
PKA (PDE4D3-specific)Upon phosphorylation, PDE4D3 is released from Ndel1Collins et al., 2008; Sette and Conti, 1996
Not reportedβ-Arrestin2Ablates dimerization and preferentially binds monomeric PDE4D5Baillie et al., 2007; Bolger, 2016; Bolger et al., 2006
  • AIP, aryl hydrocarbon receptor-interacting protein; CC2D1A, coiled-coil and C2 domain-containing protein 1A; PIASy, protein inhibitor of activated STAT protein gamma; PI3Ky, phosphoinositide 3-kinase gamma.