The CK1 family of serine/threonine protein kinases were one of the first kinases to be discovered some 50 years ago, principally because of their incessant ability to phosphorylate the milk protein casein in the test tube. Although it has turned out that this is not their actual role in biology, they have been found to impact many cellular processes, including the cell’s ability to grow, differentiate and respond to different signals. CK1 members can control all of these processes by their ability to phosphorylate many effector proteins in different subcellular compartments within the cell. However, the mechanisms by which CK1 isoforms are taken to specific subcellular compartments and their targets have remained a mystery.
Researchers from the Sapkota lab have now uncovered the secrets of how CK1 members are regulated in cells. These findings are published in the current issue of Science Signaling.
They discovered that the FAM83 family of poorly characterised proteins interact with distinct members of the CK1 family. Furthermore, they found that different FAM83 members target the interacting CK1 members to unique and distinct subcellular compartments. Excitingly, when the interactions between FAM83 proteins and CK1 was disrupted, the cellular functions of the CK1 members was compromised. For example, FAM83G activates a signalling pathway known as Wnt by regulating the activity of CK1a but fails to do so when a mutation disrupts its association with CK1a (see here).
Such a regulatory mode has also been described for protein kinase A (PKA). The A-kinase anchoring proteins (AKAPs) serve as critical regulators of PKA in cells by anchoring PKA to distinct subcellular locations.
“This is a very exciting discovery, and explains how CK1 members are regulated in cells in order to orchestrate distinct cellular functions,” says Dr Gopal Sapkota, adding, “the challenge now is to identify how each FAM83 member regulates specific subsets of CK1 targets in cells and how the regulatory network fails in human diseases.”
Luke Fulcher, a PhD student in the Sapkota lab and the lead author of the manuscript, said, “I’ve been working on the biochemistry of the FAM83:CK1 interactions since joining the lab in 2016,” adding, “it has been very interesting and rewarding to study these interactions in more detail, and everyone in the lab working on FAM83 proteins have contributed to these findings.”
This work was a huge collaborative effort, with contributions from many members of the Sapkota lab as well as the labs of Jim Smith (The Francis Crick Institute) and Alex Bullock (Structural Genomics Consortium, Oxford University). The MRC PPU proteomic, cloning, protein and antibody production teams also made significant contributions to the study.