Ras GTPases: integrins' friends or foes?

As the main surface receptors that connect cells to the extracellular matrix (ECM), integrins control cell adhesion and migration — the fundamental cell behaviours that underlie development, immune responses and tumorigenesis in animals. As the essential link between ECM and cytoskeleton, integrins relay signals from the ECM to prompt intracellular signal cascades as well as to reshape cell topology in a process termed 'outside–in' signalling. But intracellular interactions can determine the affinity of integrins for their ligands through 'inside–out' signalling. Ras proteins are small GTPases that alternate between GTP-bound and GDP-bound forms, which correspond to their active and inactive conformations, respectively. Ras proteins impart profound effects on the affinity and avidity of integrins. Ras, R-ras and Rap1 are the best studied in this respect. H-ras can either suppress or activate integrin, depending on cellular context and the type of integrin it affects. Raf1 and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) might mediate the suppression of integrins by Ras under certain circumstances, whereas phosphatidylinositol 3-kinase (PI3K) could enable Ras to activate integrins. R-ras is an activator of integrins that can convert suspension cells into highly adherent ones. R-ras employs PI3K to effect its activation of integrins in haematopoietic cells, but not in fibroblasts. Like R-ras, Rap1 is an integrin activator. Rap1 can maintain integrins in their active conformation and can promote integrin clustering to enhance avidity. RapL, a newly identified Rap1 effector, might connect Rap1 and integrin in lymphocytes. There is substantial crosstalk among Ras proteins in their regulation of integrin. R-ras counters the suppressive effect of Ras on integrins in fibroblasts. R-ras might also activate integrins through Rap1. As the main surface receptors that connect cells to the extracellular matrix (ECM), integrins control cell adhesion and migration — the fundamental cell behaviours that underlie development, immune responses and tumorigenesis in animals. As the essential link between ECM and cytoskeleton, integrins relay signals from the ECM to prompt intracellular signal cascades as well as to reshape cell topology in a process termed 'outside–in' signalling. But intracellular interactions can determine the affinity of integrins for their ligands through 'inside–out' signalling. Ras proteins are small GTPases that alternate between GTP-bound and GDP-bound forms, which correspond to their active and inactive conformations, respectively. Ras proteins impart profound effects on the affinity and avidity of integrins. Ras, R-ras and Rap1 are the best studied in this respect. H-ras can either suppress or activate integrin, depending on cellular context and the type of integrin it affects. Raf1 and extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) might mediate the suppression of integrins by Ras under certain circumstances, whereas phosphatidylinositol 3-kinase (PI3K) could enable Ras to activate integrins. R-ras is an activator of integrins that can convert suspension cells into highly adherent ones. R-ras employs PI3K to effect its activation of integrins in haematopoietic cells, but not in fibroblasts. Like R-ras, Rap1 is an integrin activator. Rap1 can maintain integrins in their active conformation and can promote integrin clustering to enhance avidity. RapL, a newly identified Rap1 effector, might connect Rap1 and integrin in lymphocytes. There is substantial crosstalk among Ras proteins in their regulation of integrin. R-ras counters the suppressive effect of Ras on integrins in fibroblasts. R-ras might also activate integrins through Rap1.