Non-glycosylated IGF2 prohormones are more mitogenic than native IGF2

TY - JOUR

T1 - Non-glycosylated IGF2 prohormones are more mitogenic than native IGF2

AU - Potalitsyn, Pavlo

AU - Mrázková, Lucie

AU - Selicharová, Irena

AU - Tencerová, Michaela

AU - Ferenčáková, Michaela

AU - Chrudinová, Martina

AU - Turnovská, Tereza

AU - Brzozowski, Andrzej Marek

AU - Marek, Aleš

AU - Kaminský, Jakub

AU - Jiráček, Jiří

AU - Žáková, Lenka

N1 - Funding Information: This work was supported by the Czech Science Foundation grant No. 19-14069S (to L.Z.), by the European Regional Development Fund, OP RDE, Project: “Chemical Biology for drugging undruggable targets (ChemBioDrug)” (No. CZ.02.1.01/0.0/0.0/16_019/0000729), by the project National Institute for Research of Metabolic and Cardiovascular Diseases (Program EXCELES, ID Project No. LX22NPO5104, Funded by the European Union-Next Generation EU), and by the Academy of Sciences of the Czech Republic (Research Project RVO:6138963, support to the Institute of Organic Chemistry and Biochemistry). A.M.B. was supported by MRC grant MR/R009066/1 and BBSRC grant BB/W003783/1. © The Author(s) 2023

PY - 2023/8/19

Y1 - 2023/8/19

N2 - Insulin-like Growth Factor-2 (IGF2) is important for the regulation of human embryonic growth and development, and for adults’ physiology. Incorrect processing of the IGF2 precursor, pro-IGF2(156), leads to the formation of two IGF2 proforms, big-IGF2(87) and big-IGF2(104). Unprocessed and mainly non-glycosylated IGF2 proforms are found at abnormally high levels in certain diseases, but their mode of action is still unclear. Here, we found that pro-IGF2(156) has the lowest ability to form its inactivating complexes with IGF-Binding Proteins and has higher proliferative properties in cells than IGF2 and other IGF prohormones. We also showed that big-IGF2(104) has a seven-fold higher binding affinity for the IGF2 receptor than IGF2, and that pro-IGF2(87) binds and activates specific receptors and stimulates cell growth similarly to the mature IGF2. The properties of these pro-IGF2 forms, especially of pro-IGF2(156) and big-IGF2(104), indicate them as hormones that may be associated with human diseases related to the accumulation of IGF-2 proforms in the circulation.

AB - Insulin-like Growth Factor-2 (IGF2) is important for the regulation of human embryonic growth and development, and for adults’ physiology. Incorrect processing of the IGF2 precursor, pro-IGF2(156), leads to the formation of two IGF2 proforms, big-IGF2(87) and big-IGF2(104). Unprocessed and mainly non-glycosylated IGF2 proforms are found at abnormally high levels in certain diseases, but their mode of action is still unclear. Here, we found that pro-IGF2(156) has the lowest ability to form its inactivating complexes with IGF-Binding Proteins and has higher proliferative properties in cells than IGF2 and other IGF prohormones. We also showed that big-IGF2(104) has a seven-fold higher binding affinity for the IGF2 receptor than IGF2, and that pro-IGF2(87) binds and activates specific receptors and stimulates cell growth similarly to the mature IGF2. The properties of these pro-IGF2 forms, especially of pro-IGF2(156) and big-IGF2(104), indicate them as hormones that may be associated with human diseases related to the accumulation of IGF-2 proforms in the circulation.

UR - http://www.scopus.com/inward/record.url?scp=85168337649&partnerID=8YFLogxK

U2 - 10.1038/s42003-023-05239-6

DO - 10.1038/s42003-023-05239-6

M3 - Article

C2 - 37598269

AN - SCOPUS:85168337649

SN - 2399-3642

VL - 6

JO - Communications Biology

JF - Communications Biology

IS - 1

M1 - 863

ER -