The STRIPAK complex

Many genes that are essential for fruiting-body formation were found by complementing sterile mutants of S. macrospora. One of them encodes PRO11, a WD40 repeat protein that can be functionally replaced by its mammalian homolog striatin. Striatins are the scaffold of the striatin-interacting phosphatase and kinase (STRIPAK) complex, which brings protein phosphatase 2A (PP2A) together with germinal center kinases and further conserved proteins. STRIPAK is found from fungi to humans and is now regarded as a fundamental signaling hub of eukaryotic development.
In S. macrospora, a homolog of the human STRIPAK complex controls sexual development. Its components include the striatin PRO11, the PP2A subunits PP2AA and SmPP2Ac1, the phocein homolog SmMOB3, the striatin-interacting protein PRO22, and SCI1, which we identified as a new component of the complex. The germinal center kinases SmKIN3 and SmKIN24 are associated with the complex. Mutants lacking STRIPAK components are sterile and impaired in hyphal fusion. The complex is therefore needed both for cell–cell fusion and for multicellular differentiation.
A central question of our current work is how STRIPAK is connected to other signaling pathways. A first hint came from a suppressor: deletion of Smgpi1, which encodes a GPI-anchored protein, restores fertility of the sterile STRIPAK mutant ΔSmmob3. More recently, proximity labeling with SCI1 as bait identified the “determinant of communication” protein SmDOC2 in the neighborhood of STRIPAK. SmDOC2 and SmDOC1 are closely tied to the pheromone response MAP kinase cascade (MIK2, MEK2, MAK2 and HAM5), and SmDOC1 interacts directly with MEK2 and MAK2. Deleting either doc gene alone severely impairs sexual development, whereas the double mutant is as fertile as the wild type. DOC1 and DOC2 thus have non-redundant, mutually antagonistic roles in the regulation of MAK2 signaling and sexual development.
Our aim is to identify the regulators and targets of STRIPAK and to understand how phosphatase, kinase and MAP kinase signaling are coordinated during hyphal fusion and fruiting-body development. Because STRIPAK is conserved, this will also help to understand cell fusion and multicellular differentiation in higher eukaryotes.