Cell Density Regulates the Golgi through Hippo, the STRIPAK Complex, and GOLPH3
The Golgi is the main hub for the modification, sorting, and transporting of proteins to various intra- and extracellular destinations. Against conventional belief that most of Golgi trafficking was constitutive, our data show regulation of Golgi morphology and trafficking in response to cell density, and extracellular cue.
Studies in our lab showed that the Golgi phosphoprotein 3 (GOLPH3) functions at the Golgi in the GOLPH3 complex to regulate Golgi trafficking. GOLPH3 is recruited to the Golgi by binding to phosphatidylInositol-4-phosphate (PI(4)P) which is enriched at the trans-Golgi. GOLPH3 also interacts with Myosin 18A (MYO18A), which in turn binds to F-actin. The linkages of PI(4)P-GOLPH3-MYO18A-F-actin make the basis of the GOLPH3 complex, which provides a tensile force applied onto Golgi membrane to aid in vesicles budding for protein transport. The consequence of that process is Golgi being stretched like an extended ribbon that surrounds the nucleus. We have shown that interfering with the GOLPH3 complex reduces cellular transport and alters Golgi morphology.
Here, we identify a signaling pathway that transduces cell density signal through the Hippo proteins MST1/2 and the STRIPAK complex to the GOLPH3 complex to regulate Golgi forward trafficking. In sparsely growing cells, MST1/2, independently of their kinase activity and the canonical Hippo pathway, act to promote the localization of Striatin 3 (STRN3) to the Golgi where STRN3 directly interacts with GOLPH3 bridging it with other members of the STRIPAK complex. The PP2A phosphatase activity of STRIPAK promotes GOLPH3’s interaction with MYO18A, which together drive Golgi forward trafficking and impart the Golgi’s normal, extended ribbon shape. On the other hand, high cell density inhibits interaction between STRIPAK complex to GOLPH3 taking away the effect of PP2A, which results in a weaken GOLPH3-MYO18A interaction. Inhibition of GOLPH3-MYO18A interaction results in compact Golgi and reduced Golgi trafficking in high cell density.
Through control of secretion, cell density signaling through MST1/2, STRIPAK, and GOLPH3 complex regulate paracrine growth factor signaling, providing a means to affect the proliferation of neighboring cells.