Understanding the mechanism of bias signaling of the insulin-like growth factor 1 receptor: Effects of LL37 and HASF.

Journal Article (Journal Article)

The development of biased agonist drugs is widely recognized to be important for the treatment of many diseases, including cardiovascular disease. While GPCR biased agonism has been heavily characterized there is a distinct lack of information with respect to RTK biased agonism both in the identification of biased agonists as well as their attendant mechanisms. One such RTK, the Insulin-like Growth Factor 1 Receptor (IGF1R) plays an important role in a range of biological and disease processes. The micropeptide LL37 has been described as a biased agonist of the IGF1R. We were interested to further understand the mechanism by which LL37 promotes biased signaling through the IGF1R. We found that LL37 biased agonism is dependent on β-arrestin 2. Moreover, BRET assays indicated that LL37 biased agonism is explained by the inability of LL37 to promote the recruitment of IRS1 to the IGF1R compared to IGF1. LL37 promotes an altered association of IGF1R with GRK6, which could also serve as an explanation for bias. We also demonstrated a functional consequence of this bias by showing that while LL37 can promote cell proliferation, it does not induce protein synthesis, unlike IGF1, which does both. We have recently identified HASF, a natural protein released by mesenchymal stem cells, as a novel ligand of the IGF1R. HASF is a paracrine factor with potent cardioprotective and cardio-regenerative properties which also acts via IGF1R biased signaling, preferentially activated ERK over Akt.

Full Text

Duke Authors

Cited Authors

  • Bareja, A; Patel, S; Hodgkinson, CP; Payne, A; Dzau, VJ

Published Date

  • June 2018

Published In

Volume / Issue

  • 46 /

Start / End Page

  • 113 - 119

PubMed ID

  • 29499305

Electronic International Standard Serial Number (EISSN)

  • 1873-3913

Digital Object Identifier (DOI)

  • 10.1016/j.cellsig.2018.02.013


  • eng

Conference Location

  • England