Insulin‐like Growth Factor [chapter]

Encyclopedia of Molecular Pharmacology  
Rat glomerular mesangial cells require laminin-9 to migrate in response to insulin-like growth factor binding protein-5. Temporal and spatial differences in extracellular matrix play critical roles in cell proliferation, differentiation and migration. Different migratory stimuli use different substrates and receptors to achieve cell migration. To understand the mechanism of insulin-like growth factor binding protein-5 (IGFBP-5)-induced migration in mesangial cells, the roles of integrins and
more » ... of integrins and substrates were examined. IGFBP-5 induced an increase in mRNA expression for laminin (LN) chains lama4, lamb2, and lamc1, suggesting that LN-9 might be required for migration. Antibodies to the LN␣ 4 and LN␤2 chains, but not LN␤1, blocked IGFBP-5-induced migration. Anti-sense morpholino oligonucleotide inhibition of expression of LN␣4 substantially reduced expression of LN-8/9 (␣ 4␤1␥1/␣4␤2␥1, 411/421) and prevented IGFBP-5-induced migration. Anti-sense inhibition of lamb2 reduced expression of LN-9. Absence of LN-9 prevented IGFBP-5-induced migration, which was not preserved by continued expression of LN-8. The requirement for LN-9 was further supported by studies of T98G cells, which express predominantly LN-8. IGFBP-5 had little effect on migration in these cells, but increased migration when T98G cells were plated on LN-8/9. IGFBP-5-mediated mesangial cell migration was inhibited by antibodies that block attachment to ␣ 6␤1-integrins but was unaffected by antibodies and disintegrins that block binding to other integrins. Furthermore, in cells with anti-sense inhibited expression of LN-9, integrin ␣ 6␤1 was no longer detected on the cell surface. These studies suggest the specificity of mechanisms of migration induced by specific stimuli and for the first time demonstrate a unique function for LN-9 in mediating IGFBP-5-induced migration. migration; integrins; extracellular matrix CELL MIGRATION plays a critical role during development, wound healing, and in response to injury. There is growing evidence that different migratory stimuli utilize specific matrix substrates, integrins, and signal transduction cascades (18, 58) . In vivo, this specificity provides migration of particular cells to the location where they are required. Growth factors and other migratory stimuli often require matrix binding to transduce their effects on cells (18). Matrix-bound growth factors interact with their receptors to modulate membrane incorporation and inside-out signaling of integrins, which activates integrins and enhances matrix attachment. Platelet-derived growth factor (PDGF) binding to laminin-5 (LN␣ 3 ␤ 3 ␥ 2 , LN-332) (6) is one of the best-studied examples (41). Prevention of matrix binding
doi:10.1007/978-3-540-38918-7_5976 fatcat:ksnl4k4j3bdvzeawnccydylni4