There are at least two interlocking systems that allow insulin to regulate gene expression:
The MAPK / ERK pathway is mainly concerned with long term tissue growth and differentiation. Many other hormones and growth factors share some of these components with insulin. It is better documented because it was discovered first.
SREBP is more concerned with the day to day control of gene expression in response to diet. Details of the SREBP pathway have only recently been published for a wide range of key enzymes, so we will include it in the course next year, but not in 2005.
The MAPK / ERK signaling pathway starts with the autophosphorylation of the insulin receptor, which in turn phosphorylates IRS-1. These first two steps are identical to those described for glucose transport and glycogen metabolism. Thereafter the pathways diverge, and phosphorylated IRS-1 forms a complex with various adaptor proteins, and the small GTPase RAS. We mention RAS here because it also has an important role in cancer. RAS has some similarity, but is not identical, to the heterotrimeric G proteins that are involved with adenyl cyclase and other hormonal signaling systems. RAS undergoes a conformational change on activation, leading to the replacement of bound GDP with fresh GTP, and like the G proteins it has only a limited duration of action. Transient action is a common feature in many signal transduction pathways, and is something that you should try to remember even if you forget the other details.
Scroll down to view the diagram, then click the buttons below for further details of the gene expression pathway.
|1||Phosphorylated IRS-1 forms a complex with Grb2, Sos and Ras|
|2||GTP turnover leads to activation of Raf-1|
|3||Activated Raf-1 phosphorylates MEK|
|4||Activated MEK phosphorylates MAPK (alias ERK)|
Activated MAPK and SREBP (not illustrated) both enter the nucleus. MAPK phosphorylates various transcription factors, while SREBP binds directly to DNA. Both proteins cause long term changes in gene expression, some of which are covered in subsequent lectures. Use the back button to return to the main document.
|ERK||extracellular regulated kinase (=MAPK)|
|Grb2||growth factor receptor bound protein 2|
|IRS-1||insulin receptor substrate 1|
|MAPK||mitogen-activated protein kinase (=ERK)|
|MEK||mitogen-activated, ERK-activating kinase|
|Raf-1||cellular oncogene, inhibits apoptosis|
|Ras||a small membrane-assocatiated GTPase|
|Sos||son of sevenless - a guanine nucleotide exchange protein|
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