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.

人们普遍认为，偏向激动剂药物的开发对许多疾病（包括心血管疾病）的治疗很重要。尽管已经高度表征了GPCR偏置激动剂，但在鉴定偏置激动剂及其伴随机制方面，都明显缺乏有关RTK偏置激动剂的信息。一种这样的RTK，即胰岛素样生长因子1受体（IGF1R）在一系列生物学和疾病过程中起着重要作用。微量肽LL37被描述为IGF1R的偏置激动剂。我们有兴趣进一步了解LL37通过IGF1R促进偏向信号转导的机制。我们发现LL37偏向激动作用取决于β-arrestin2。此外，BRET分析表明，与IGF1相比，LL37无法促进IRS1向IGF1R的募集可以解释LL37的激动作用。LL37促进了IGF1R与GRK6的关联改变，这也可以作为偏见的解释。我们还通过证明LL37可以促进细胞增殖，却不像IGF1那样诱导蛋白质合成，来证明这种偏见的功能性后果。我们最近鉴定出HASF（一种由间充质干细胞释放的天然蛋白质）作为IGF1R的新型配体。HASF是具有有效的心脏保护和心脏再生特性的旁分泌因子，它还通过IGF1R偏向信号传导（优先于Akt激活ERK）起作用。这也可以用来解释偏见。我们还通过证明LL37可以促进细胞增殖，却不像IGF1那样诱导蛋白质合成，来证明这种偏见的功能性后果。我们最近鉴定出HASF（一种由间充质干细胞释放的天然蛋白质）作为IGF1R的新型配体。HASF是具有有效的心脏保护和心脏再生特性的旁分泌因子，它还通过IGF1R偏向信号传导（优先于Akt激活ERK）起作用。这也可以用来解释偏见。我们还通过证明LL37可以促进细胞增殖，却不像IGF1那样诱导蛋白质合成，来证明这种偏见的功能性后果。我们最近鉴定出HASF（一种由间充质干细胞释放的天然蛋白质）作为IGF1R的新型配体。HASF是具有有效的心脏保护和心脏再生特性的旁分泌因子，它还通过IGF1R偏向信号传导（优先于Akt激活ERK）起作用。作为IGF1R的新型配体。HASF是具有有效的心脏保护和心脏再生特性的旁分泌因子，它还通过IGF1R偏向信号传导（优先于Akt激活ERK）起作用。作为IGF1R的新型配体。HASF是具有有效的心脏保护和心脏再生特性的旁分泌因子，它还通过IGF1R偏向信号传导（优先于Akt激活ERK）起作用。