Figure 3.

The cAMP–PKA pathway that controls filamentation in Saccharomyces cerevisiae and Candida albicans. A schematic representation of the pathway in (A), S. cerevisiae and (B) C. albicans. PKA is a complex of the form R₂C₂ which activates filamentation. The R subunits are constituted by Bcy1 while the C subunits may be any two of Tpk1/Tpk2/Tpk3 in S. cerevisiae and Tpk1/Tpk2 in C. albicans. When cAMP is produced, it binds to Bcy1 and releases the active C subunits which phosphorylate downstream transcription factors and activate them. Depending on the C subunits released, the downstream targets vary. The production of cAMP is made possible by the adenylyl cyclase (Cyr1) which coverts ATP to cAMP. Any excess cAMP is degraded by phosphodiesterases (Pde2/Pde1). Pde2 (in bold) is the dominant player. Cyr1 is regulated by the binding of Ras2/Ras1 in S. cerevisiae and by Ras1 in C. albicans. It is also activated by Srv2/CAP1 and the binding of monomeric G-actin to the latter. In S. cerevisiae, heat shock proteins Hsc82 (or Hsp82) along with the co-chaperone, Sgt1, promote the interaction between Ras2 and Cyr1, whereas in C. albicans, Hsp90-Sgt1 inhibits Ras1–Cyr1 interaction. Ras proteins require to be in their active GTP-bound form for an effective interaction with Cyr1. For this, the GDP-bound inactive form of Ras must first be activated by the GEF, Cdc25 to the GTP-bound form. Ras cycles back to its inactive state by interacting with GAPs, Ira1/Ira2 in S. cerevisiae and Ira2 in C. albicans. This interaction can be blocked by a Gly19Val mutation in S. cerevisiae Ras2 and Gly13Val mutation in C. albicans Ras1, producing constitutively activated Ras proteins. PM localization of Ras proteins is dependent on their farnesylation in the cytoplasm and palmitoylation at the ER. Gpr1-Gpa2 is a G-protein–coupled receptor-G-protein pair required to transport glucose (S. cerevisiae) or lactose/Met (C. albicans). Phosphorylated Gpa2 can activate Cyr1. The conversion of glucose to fructose 1,6-bis-phosphate (Fru1,6bisP) activates Cdc25 and turns on Ras-dependent Cyr1-cAMP-PKA signaling in S. cerevisiae. It is hypothesized that a similar mechanism operates in C. albicans. CO₂-mediated activation of Cyr1 is exclusive to C. albicans and occurs independent of Ras1–Cyr1 interaction. Double headed arrows represent protein–protein interactions, the red flatheaded arrows represent inhibition, and the blue arrows represent activation.