Ras GTPases: integrins' friends or foes?

  • A Correction to this article was published on 01 January 2004


Integrins are cell-surface receptors that mediate and coordinate cellular responses to the extracellular matrix (ECM). Cellular signalling pathways can regulate cell adhesion by altering the affinity and avidity of integrins for ECM. The Ras family of small G proteins, which includes H-ras, R-ras and Rap, are important elements in cellular signalling pathways that control integrin function.

Key Points

  • 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.

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Figure 1: Schematic of integrin interaction with ECM and intracellular proteins.
Figure 2: H-ras-mediated integrin regulation in fibroblasts.
Figure 3: Rap-mediated integrin activation.


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K.K., L.E.G., M.H. and F.L.C. are supported by postdoctoral fellowships from the University of California Tobacco-Related Disease Program, the American Cancer Society, the Danish Medical Research Council and the American Heart Association, respectively. Research in the Ginsberg laboratory is supported by the National Institutes of Health.

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Correspondence to Mark H. Ginsberg.

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Integrin α

Integrin β














Integrin α1

Integrin αIIb

Integrin α4

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Integrin α6

Integrin αM

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Integrin β2

Integrin β3







The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex.


A carboxy-terminal tetrapeptide that is common to all Ras proteins and that directs a triplet of post-translational modifications.


The carboxy-terminal 25 amino acids of H-, N- and K-ras proteins in which sequence homology is less than 15% between any two isoforms compared with 90–100% over the amino-terminal sequences.


A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.


A type of white blood cell that has a bi-lobed nucleus and large cytoplasmic granules — containing hydrolytic enzymes — that stain readily with eosin.


The structures of Ras proteins resolved in either GDP- or GTP-bound form showed that the conformational change resulting from nucleotide exchange is mostly confined to the loop L2-β2 (according to Ras structural nomenclature) and the β3/α2 regions, which are termed switch I and II regions.


Any cell of the mononuclear phagocyte system that is characterized by its ability to phagocytose foreign particulate and colloidal material.


The process by which microorganisms or other particulate material are rendered more susceptible to phagocytosis by coating with opsonin.


A protein that augments cellular responses by recruiting other proteins to a complex. Adaptor proteins usually contain several protein–protein interaction domains.


(Src-homology-3 domain). Protein sequences of about 50 amino acids that recognize and bind sequences that are rich in proline.


Ras proteins with mutations in their effector-binding domains that abrogate their interactions with specific effectors.


A sequence of 100 amino acids that is present in many signalling molecules and binds to lipid products of phosphatidylinositol 3-kinase. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.


The strength of binding, usually of multiple ligand–receptor complexes in aggregation.


The source of blood platelets. The platelets are released by the megakaryocyte into the capillary sinuses. They are the largest cells in normal bone marrow.


The antigen-binding fragment of an immunoglobulin molecule. It is used when multimerization of antibodies caused by their Fc domains is not desirable.

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