Signaling Size: Ankyrin and SOCS Box-Containing ASB E3 Ligases in Action

• Published in: Trends in biochemical sciences (Amsterdam. Regular ed.) Vol. 44; no. 1; pp. 64 - 74
• Main Authors: Liu, Pengyu, Verhaar, Auke P., Peppelenbosch, Maikel P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2019
• Subjects: amino acids; Animals; Ankyrins - metabolism; Asb subgroup; brain; compartment size; cytokines; Humans; ligases; mitochondria; muscle; muscles; Notch signaling; pathophysiology; physiology; Pongidae; Signal Transduction; Suppressor of Cytokine Signaling Proteins - metabolism; ubiquitin; Ubiquitin-Protein Ligases - metabolism; ubiquitination; compartment size; Asb subgroup; Notch signaling; ubiquitination; muscle
• ISSN: 0968-0004; 1362-4326
• DOI: 10.1016/j.tibs.2018.10.003

Ankyrin repeat and suppressor of cytokine signaling (SOCS) box (Asb) proteins are ubiquitin E3 ligases. The subfamily of six-ankyrin repeat domain-containing Asb proteins (Asb5, Asb9, Asb11, and Asb13) is of specific interest because they display unusual strong evolutionary conservation (e.g., urochordate and human ASB11 are >49% similar at the amino acid level) and mediate compartment size expansion, regulating, for instance, the size of the brain and muscle compartment. Thus, they may be involved in the explanation of the differences in brain size between humans and apes. Mechanistically, many questions remain, but it has become clear that regulation of canonical Notch signaling and also mitochondrial function are important effectors. Here, we review the action and function of six ankyrin repeat domain-containing Asb proteins in physiology and pathophysiology. ASBs are a family of E3 ubiquitin ligases. Within this family, the six-ankyrin repeat domain-containing ASBs (ASB5, ASB9, ASB11, and ASB13) are a distinct group because they are evolutionary the most ancient ASBs and show unusually high conservation (Ciona intestinalis and human ASB11 being >49% identical at the amino acid level). ASBs act by modification of Notch signaling and mitochondrial function, whereas, in physiology, their most fascinating function is their role in the regulation of compartment size. ASB11 has been subject to positive selection during evolution from a chimpanzee-like ancestor to humans and this may be important for explaining the concomitant increase in brain size. ASB-driven compartment size expansion is linked to cancer and morbid obesity, among other pathological conditions.