Description
Insulin signaling pathway plays essential roles in glucose and energy homeostasis. Insulin binding to its receptor triggers receptor autophosphorylation of a number of tyrosine residues on the juxtamembrane, kinase and C-terminal domains. The phosphotyrosines allow for the recruitment and subsequent phosphorylation of various receptor substrates including Irs1 and 2, and Shc1. The phosphorylated substrates serve as docking sites for the binding of selected partners and the activation of downstream signaling cascades, primarily the PI3K-Akt and the Ras mediated Raf/Mek/Erk pathways. The SH2 (
src homology 2) domains of p85 - the regulatory subunit of PI3K - and of Grb2 bind to Irs and Shc1, respectively. Via its N-terminal SH3 (
src homology 3) domain, Grb2 associates with Sos (guanine nucleotide exchange factor for Ras), to activate Ras and the downstream Raf/Mek/Erk MAPK pathway. Both the autophosphorylation and the substrate driven kinase activities of the insulin receptor are tightly regulated. Enpp1 and Ptpn1 inhibit the former, members of the Grb adaptor proteins (Grb10, Grb14) and of the Socs family (Socs1, Socs3, Socs6) inhibit the latter. Note that members of the Socs family also inhibit leptin pathway, particularly Socs3 whose expression is under the control of Stat3 acting downstream of the leptin activated Jak2. While PI3K is a main signaling pathway downstream of insulin and the particular Jak2-Stat3 combination is the main downstream effector of leptin, leptin mediated activation of Jak2 can also trigger PI3K via Irs phosphorylation by Jak2. In the brain, both leptin and insulin act to increase the expression of
Pomc while decreasing the expression of
Agrp genes albeit through different mechanisms.
Pomc and
Agrp express appetite decreasing/increasing products, respectively.
Abbreviations
Irs – insulin receptor substrate
Shc1 - src homology 2 domain-containing transforming protein C1
PI3K – phosphatidylinositol 3-kinase
Grb – growth factor receptor-bound
Sos – son of sevenless homolog
Enpp1 - ectonucleotide pyrophosphatase/phosphodiesterase 1
Ptpn1 – protein tyrosine phosphatase, non-receptor type 1
Ptprf - protein tyrosine phosphatase, receptor type, F
Socs – suppressors of cytokine signaling
Jak – Janus-activated kinase
Stat – signal transducers and activators of transcription
Pomc - pro-opiomelanocortin gene
Agrp - agouti-related protein gene
References
PMID:17010638, 16493415, 17347799, 16823473, 15901248
