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 α5β1 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 α5 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.
Abbreviations used: ECM, extracellular matrix; Erk, extracellular-signal-regulated kinase; ETS, E twenty-six; JNK, c-Jun N-terminal kinase; MAP, mitogen-activated protein; MEK, MAP kinase/Erk kinase; PAK, p21-activated kinase; PKA, protein kinase A; RTK, receptor tyrosine kinase; SH2 domain, Src homology 2 domain.
Molecular Environment of Integrins: a Biochemical Society Focused Meeting held at Chancellors Conference Centre, University of Manchester, 1–3 December 2003