11. Insulin Receptor

 

Insulin and IGF-1 receptors are homologous to tyrosine kinase receptors (Boucher J et al., 2014).  

 

Insulin receptor (IR) and IGF-1 receptor (IGF-1R) include two extracellular α subunits and two transmembrane β subunis, which are connected by disulfide bonds (Boucher J et al., 2014).

 

11.1. PIP3 and PI3K and Related Downstream Pathway 

 

PI3K and AKT/ PKB (protein kinase B) signaling pathway is an important pathway, which plays role in partaking of IRS (Insulin Receptor Substrate) in insulin metabolic functions (Boucher J et al., 2014).

 

As IRS is tyrosine phosphorylated then PI3K is induced and results in the activation of PIP2 and production of PIP3, which causes the AKT/PKB deployment to the plasma membrane and promotes its phosphorylation and induction and ultimately the stimulation of downstream signaling pathway (Myers M G Jr et al., 1992) (Shaw L M., 2011) (Boucher J et al., 2014).

 

AGG family of protein kinases, which are controlled by PI3K are phosphorylated and activated by PDK-1 (3-phosphoinositide-dependent protein kinase-1) (Bayascas J R., 2010 as cited in Boucher J et al., 2014) (Boucher J et al., 2014). It is also known that phosphorylation of PKCs by PDK-1 is responsible for the induction of aPKCs (atypical PKCs), PKCζ and PKCλ/ι (Boucher J et al., 2014). Glucose transport, prompted by insulin and control of lipid synthesis is regulated by aPKC  (Boucher J et al., 2014).

 

In order to fully activate AKT/PKB, then mTORC2 needs to phosphorylate this protein kinase at Ser-473 (Sarbassov D D et al., 2005 as cited in Boucher J et al., 2014) (Oh W L and Jacinto E., 2011) (Boucher J et al., 2014). 

 

Impairment of DNA results in phosphorylation and activation of AKT/PKB by DNAPK (DNA-dependent protein kinase), which plays a part in controlling fatty acid synthease (a metabolic gene) activities through insulin (Bozulic L et al., 2008) (Wong R H F et al., 2009) (Boucher J et al., 2014).

 

Furthermore, phosphorylation of GSK3 (Glycogen Synthase kinase 3) and its inhibition is regulated by AKT/PKB and is responsible for the induction of glycogen synthase (Kim K H et al., 2004) (Boucher J et al., 2014).

 

Insulin Receptor References

 

1.        Bayascas, J. R. PDK1: The Major Transducer of PI 3-Kinase Actions. in 9–29 (2010). doi:10.1007/82_2010_43

2.        Boucher, J., Kleinridders, A. & Kahn, C. R. Insulin Receptor Signaling in Normal and Insulin-Resistant States. Cold Spring Harb. Perspect. Biol. 6, a009191–a009191 (2014).

3.        Bozulic, L., Surucu, B., Hynx, D. & Hemmings, B. A. PKBα/Akt1 Acts Downstream of DNA-PK in the DNA Double-Strand Break Response and Promotes Survival. Mol. Cell 30, 203–213 (2008).

4.        Kim, K. H. et al. Regulatory Role of Glycogen Synthase Kinase 3 for Transcriptional Activity of ADD1/SREBP1c. J. Biol. Chem. 279, 51999–52006 (2004).

5.        Myers, M. G. et al. IRS-1 activates phosphatidylinositol 3’-kinase by associating with src homology 2 domains of p85. Proc. Natl. Acad. Sci. 89, 10350–10354 (1992).

6.        Oh, W. J. & Jacinto, E. mTOR complex 2 signaling and functions. Cell Cycle 10, 2305–2316 (2011).

7.        Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and Regulation of Akt/PKB by the Rictor-mTOR Complex. Science (80-. ). 307, 1098–1101 (2005).

8.        Shaw, L. M. The insulin receptor substrate (IRS) proteins. Cell Cycle 10, 1750–1756 (2011).

9.        Wong, R. H. F. et al. A Role of DNA-PK for the Metabolic Gene Regulation in Response to Insulin. Cell 136, 1056–1072 (2009).