Mesangial cell proliferation is an early event in several progressive renal diseases. When mesangial cells in culture are rendered quiescent by serum starvation and subsequently stimulated to proliferate, induction of c-fos is an early indicator of entry into the cell cycle. Several heparin-sensitive signals transduce these events. We have examined the potential roles of Ca²⁺/calmodulin-dependent kinase (CaMK) and cAMP-dependent kinase (PKA). Selective stimulation of CaMK with Ca²⁺ ionophores, and of PKA with forskolin or dibutyryl cAMP both result in induction of c-fos mRNA. CaMK, but not PKA signaling is suppressed by low concentrations of heparin. Cross talk between the pathways has been demonstrated in some cells, with evidence of CaMK phosphorylating cAMP response element binding protein (CREB) at an inhibitory site, and PKA suppressing CaMK-dependent signaling. However, in the present study, both pathways phosphorylated CREB on Ser¹³³, and induced c-fos in an additive manner. Serum, Ionomycin, and forskolin all caused a rapid decline in cyclin D1 levels, but only serum effected a subsequent increase, indicative of cell cycle progression. We conclude that, in human mesangial cells, CaMK and PKA can both contribute to cell cycle entry, and while induction of c-fos by CaMK requires active PKA, neither pathway antagonizes or synergizes c-fos induction by the other.