Schematic representation of a model of the PKCζ regulation by cAMP and SDF-1/CXCR4. Cellular cAMP accumulation is induced by the ligands (eg, PGE2) that activate Gα_s-coupled receptors. Persistent (“prolonged” hours) stimulation with the cAMP-elevating agents results in PKCζ activation in a Rap1/Rac1-dependent manner and a subsequent increase in membranal CXCR4 expression. CXCR4 binding to SDF-1 further activates PKCζ, resulting in a positive feedback loop. On the other hand, SDF-1/CXCR4 interactions might reduce the cellular cAMP level as a result of Gα_i activity, establishing a negative feedback loop on the cAMP-induced PKCζ activation. SDF-1 activates PKCζ by a distinct from the cAMP, PI3K-dependent pathway.¹⁷  PKCζ activity is required for multiple cellular functions, including MMP-2/MMP-9 secretion, motility, adhesion, and survival. cAMP reduces cell proliferation in a PKCζ-independent manner because of a negative effect on ERK1/2 activity. In contrast to “prolonged” cAMP activation, “short” (minutes) priming with the cAMP-elevating agents antagonizes PKCζ-mediated SDF-1/CXCR4-induced responses.