IGF-I: a mitogen also involved in differentiation processes in mammalian cells.
The main source of insulin-like growth factor I (IGF-I) postnatally is the liver, under growth hormone stimulation, although IGF-I is already present in embryonic tissues and in fetal serum, when its expression is independent of growth hormone. The extracellular alpha-subunit of the IGF-I receptor (IGF-IR) contains an IGF-I binding domain, and the beta-subunit possesses tyrosine kinase activity, which is greatly enhanced when IGF-I binds to the alpha-subunit and leads to its autophosphorylation. Insulin receptor substrate 1 (IRS-1) is the most well characterized cellular substrate for IGF-I, containing at least 20 potential tyrosine phosphorylation sites. The tyrosine phosphorylated form of IRS-1 acts as a docking protein by associating SH2-containing proteins including the p85 regulatory subunit of phosphatidylinositol-3-kinase (P13-kinase), the protein tyrosine phosphatase SH-PTP2, the SH2- and SH3-containing adaptor protein Nck and the growth factor receptor-bound protein-2 (Grb2/Sem5) protein. Grb2 is found associated with mSOS, a GTP/GDP exchange factor involved in converting the inactive Ras-GDP to the active Ras-GTP. The p85 regulatory subunit of PI3-kinase can be also a direct in vitro substrate of the IGF-IR. Although IRS-1 is the major substrate of the IGF-IR, there is another early phosphotyrosine substrate termed SHC, which also activates Ras via Grb2-mSos complex. Activation of p21-Ras induces a serine/threonine kinase cascade leading to the activation of MAP-kinases. The importance of IGF-I as a mitogen throughout development has been clearly demonstrated in IGF-I and IGF-IR knockout mouse studies and also in transgenic mice over-expressing IGF-I. IGF-I is a mitogen in many cell types in culture such as T lymphocytes, chondrocytes or osteoblasts and it is considered to be a progression factor in mouse fibroblasts. IGF-I is also involved in muscle, neurons and adipogenic differentiation of mesenchymal cells. However, IGF-I induces proliferation and differentiation in fetal brown adipocytes, suggesting that both cellular processes are not necessarily mutually exclusive in fetal cells.
Benito
M
M
Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense, Madrid, Spain.
Valverde
A M
AM
Lorenzo
M
M
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D005314:Embryonic and Fetal Development / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000502:physiology*; D008322:Mammals / Q000196:embryology / Q000502:physiology*; D008934:Mitogens / Q000502:physiology*; D051381:Rats; D017451:Receptors, Somatomedin / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013329:Structure-Activity Relationship
D008934:Mitogens; D017451:Receptors, Somatomedin; D007334:Insulin-Like Growth Factor I