Integrin regulation of cell signalling and motility.
Integrins clearly play a key role in regulating both mitogenic signalling and cell migration. Thus integrins modulate the efficiency of the Erk (extracellular-signal-regulated kinase)/MAP kinase (mitogen-activated protein kinase) pathway, acting at several distinct levels. We have shown that both cAMP-dependent protein kinase and PAKs (p21-activated kinases) play a role in integrin regulation of the Erk pathway, acting primarily at the level of Raf-1. Integrins and PAKs also play a role in the control of cell migration. Thus we have discovered a novel protein that links the alpha5beta1 integrin to migration controlled by Rho-family GTPases. This protein, termed Nischarin, is a large cytosolic macromolecule that is not related to well-known protein families. The N-terminus of Nischarin interacts with a short segment of the cytoplasmic domain of the alpha5 integrin subunit. Overexpression of Nischarin alters actin organization and inhibits Rac-driven cell migration and tumour cell invasion. Use of effector domain mutants of Rac suggest that Nischarin acts downstream of Rac, probably at the level of PAK-family kinases. These studies emphasize the intricate connection between integrins and Rho-family GTPases and their effectors in controlling both mitogenesis and migration.
Juliano
R L
RL
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA. arjay@med.unc.edu
Reddig
P
P
Alahari
S
S
Edin
M
M
Howe
A
A
Aplin
A
A
D000818:Animals; D002465:Cell Movement; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D054755:Imidazoline Receptors; D016023:Integrins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry; D015398:Signal Transduction
D054755:Imidazoline Receptors; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; C458505:NISCH protein, human; D011506:Proteins; D048052:Mitogen-Activated Protein Kinase 3