ANKRD26 and Its Interacting Partners TRIO, GPS2, HMMR and DIPA Regulate Adipogenesis in 3T3-L1 Cells

Abstract

Partial inactivation of the Ankyrin repeat domain 26 (Ankrd26) gene causes obesity and diabetes in mice and increases spontaneous and induced adipogenesis in mouse embryonic fibroblasts. However, it is not yet known how the Ankrd26 protein carries out its biological functions. We identified by yeast two-hybrid and immunoprecipitation assays the triple functional domain protein (TRIO), the G protein pathway suppressor 2 (GPS2), the delta-interacting protein A (DIPA) and the hyaluronan-mediated motility receptor (HMMR) as ANKRD26 interacting partners. Adipogenesis of 3T3-L1 cells was increased by selective down-regulation of Ankrd26, Trio, Gps2, Hmmr and Dipa. Furthermore, GPS2 and DIPA, which are normally located in the nucleus, were translocated to the cytoplasm, when the C-terminus of ANKRD26 was introduced into these cells. These findings provide biochemical evidence that ANKRD26, TRIO, GPS2 and HMMR are novel and important regulators of adipogenisis and identify new targets for the modulation of adipogenesis.

Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation

“…In various MK cell lines, the induction of differentiation in response to PMA or TPO showed a rapid and sustained activation of ERK1/2 (26)(27)(28)(29), suggesting that the MAPK/ERK1/2 pathway plays an important role in MK differentiation. Similar results were obtained in human and ANKRD26 is localized in the inner part of the cell membrane and can interact with transmembrane receptors (31). An attractive hypothesis would be that ANKRD26 controls MPL signaling through its trafficking.…”

Improving diagnostic precision, care and syndrome definitions using comprehensive next-generation sequencing for the inherited bone marrow failure syndromes

“…For example, one of two patients with FT (see online supplementary table S3, patients 38 and 39) had a mutation in MYH9 , leading to a specific diagnosis of MYH9 -associated FT, while the other was classified as having ANKRD26 -associated FT, based on having a frameshift mutation in the ANKRD26 gene. This frameshift causes loss of the last 50 amino acids of the protein, a region that is critical for the binding of ANKRD26 to its partner, TRIO, that shares cellular functions with ANKRD26 18. Importantly, in contrast to MYH9 -associated FT, ANKRD26 -associated FT is associated with an increased risk of haematological malignancies19 and indicates cancer surveillance 20…”

Receptor for hyaluronan mediated motility (RHAMM/HMMR) is a novel target for promoting subcutaneous adipogenesis

“…Furthermore, intracellular RHAMM protein isoforms complex with, sustain activity and regulate subcellular targeting of the MEK1/ERK1,2 complexes that affect adipogenesis [38]. Intracellular RHAMM also partners with anti-adipogenic proteins such as the ERK1,2 target protein ANKRYD26[39, 78], which results in suppression of the activation and expression of master adipogenic transcription factors such as PPARγ[79]. …”

“…ERK1) [36, 37] while intracellular RHAMM partners with and regulates ERK1 activity and subcellular distribution[38]. Intracellular RHAMM also partners with ANKRYN26, a protein that suppresses adipogenesis[36, 39]. We reasoned that blocking RHAMM signaling functions in skin would promote subcutaneous adipogenesis for use as a tool in tissue engineering, for treating lipodystrophies and for managing other metabolic diseases.…”