M. Fenger¹, S.B. Haugaard², O. Andersen³, S. Masdbad⁴, T. Werge⁵ and A. Linneberg⁶

¹University of Copenhagen, Denmark and Department of Clinical Biochemistry, Capital Hospitals of Denmark at Hvidovre. ²Department of Endocrinology and Clinical Research Centre, Capital Hospitals of Denmark at Hvidovre. ³Clinical Research Centre, Capital Hospitals of Denmark at Hvidovre. ⁴Department of Endocrinology Capital Hospitals of Denmark at Hvidovre. ⁵Psychiatric Research Centre, Skt. Hans Hospital, Roskilde, Denmark. ⁶Research Centre for Prevention and Health, Glostrup, Denmark.

Abstract

Glycogen synthase kinase 3β (GSK3β) was discovered as a major factor in glucose homeostasis. GSK3β is a pivotal regulator of glycogen synthesis by altering the activity of glycogen synthase and perturbation in this process have been linked to at least some sub-entities of insulin resistance and diabetes mellitus. However, GSK3β has a central role in many biochemical and physiological processes apparently not related to insulin resistance or diabetes. The functionality of GSK3β is vast including more than 33 substrates and 72 protein-protein interactions, and is involved in such diverse diseases as cancer, schizophrenia, inflamation, cardiac diseases and many more. Considering this scale of the involvement of GSK3β, many related to developmental processes, suggests that either is GSK3β a high-level network-hub or is a peripheral kinase in several non-connected networks. Here, evidence is provided that GSK3β is an ultraconserved protein which would suggest that the enzyme qualify to be a kernel protein in the sense that life as we know it depends on conserved molecular entities to provide the essential functionality to an organism. The enzyme has evolved under strong purifying selection implicating that GSK3β is a functional hub.