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IGF1R, a receptor to IGF1, is expressed by all cells and tissues except the hepatocyte. It has been shown that IGF1R exists in a variety of cells and tissues. Thus, it can be found in various vital movement including normal and pathological physiological process. IGF1R and insulin receptor are produced in the same cells, and their structure is highly homologous to each other.
Structure and function of IGF1R
Researches about IGF1R and insulin revealed that some of them form a hybrid receptor comprised of an insulin receptor and an IGF1R, illustrating like Figure 1.
Figure 1. Schematic illustration of IGF1R/insulin receptor. (Fumihiko Hakuno et al. 2018)
Structure studies about IGF1R show that it is a disulfide bond-conjugated tetramer composed of two α subunits that are extracellular proteins binding to specific ligands and two β subunits that are transmembrane proteins possessing tyrosine kinase activity. The β subunit conformation will change when IGF1R bind with IGFs, activating the activity of receptor tyrosine kinase. Some of the tyrosine residues of β subunit are possibly phosphorylated. It is shown that the phosphorylation of tyrosine is caused by tyrosine kinase of another β subunit of the tetrameric IGF1R. The β subunit can be recognized by docking proteins, like IRSs which possess the phosphotyrosine binding (PTB) domain, then bound to it, when the tyrosine residue is phosphorylated. Following, the docking proteins are phosphorylated.
IGF1R and related signaling pathways
In addition, studies found that the stimulation of IGF1 can prolonged association of PI 3-kinase with IGF1R. Furthermore, the fact that tyr1316-X-X-Met of IGF1R functioned as a PI 3-kinase-binding sequence when this tyrosine is phosphorylated has been demonstrated. Previous researches suggested that the IGF1R and insulin receptor are not interchangeable. In addition, specific regions have importance in control of various functions within the C-terminus of them, and the C-terminal region of IGF1R is shown to relate to various proteins such as Grb10, receptor for activated C kinase 1 (RACK1), focal adhesion kinase, jun N-terminal kinase (JNK), tissue inhibitor of metalloproteinase 2 (TIMP2), janus jinase 1/2 (JAK1/2) and suppressor of cytokine signaling 1/2/3 (SOCS1/2/3), which may affect specificity and mediate or modulate IGF1R signaling.
Moreover, multiple modifications of IGF1R are also reported. Two lysine residues in the IGF1R activation loop can promote the internalization and downregulation of the receptor. In addition, a variety of serine/ threonine residues of IGF1R are phosphorylated, and some of them are important for IGF1R to bind with signaling molecules. For instance, phosphorylation of serine 1291 induces the binding of IGF1R with β-arrestin 1, leading to degradation of the receptors as well as activation of the downstream pathway, like the MAP kinase pathway. Some reports also found that UMOylation of IGF1R causes its nuclear transport, resulting in tyrosine phosphorylation of histone.
The function studies about IGF1R suggest that it is a marker of cancer stem cells (CSCs). By detecting the expression of Oct-4 and Nanog transcription factors, reports reveal that the IGF1R signaling plays important roles in maintaining “stemness” of CSCs. And IGF1R also can be activated by IGF2, which is secreted by cancer-associated fibroblasts. Additionally, some reports also point out that IGF1R inhibit ASK1 resulting in activation of cell proliferation, survival, and inhibition of cell death.