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Integrin signalling adaptors: not only figurants in the cancer story

Key Points

  • In cancer cells, integrin and growth factor receptor crosstalk leads to the recruitment of integrin signalling adaptors to assemble intracellular signalling platforms that result in cellular transformation and the control of migration and invasion. The biological effects that are regulated by integrin adaptors are dependent on their expression levels and on their phosphorylation status, which determine the association with binding effectors.

  • p130 Crk-associated substrate (p130CAS; also known as BCAR1), neural precursor cell expressed, developmentally down-regulated 9 (NEDD9; also known as HEF1), CRK, the integrin-linked kinase (ILK)–pinch–parvin (IPP) complex and p140 Cas-associated protein (p140CAP; also known as SRCIN1) integrin adaptors have a profound influence on all aspects of cancer progression, including initiation, progression and metastasis. Transgenic and xenograft animal models support the crucial role of these integrin adaptors in tumorigenesis.

  • In several human tumours, high expression of p130CAS, NEDD9, CRK, ILK, PINCH1 and PINCH2 correlates with increased disease progression, and the levels of parvin-β and p140CAP proteins are inversely correlated with malignancy. Current knowledge also implicates integrin adaptors in acquired resistance to cancer treatment.

  • In cancer cells, at the molecular level, these adaptors regulate signalling pathways that are required for the control of cell proliferation, survival and for actin cytoskeleton organization and extracellular matrix degradation. These events are fundamental for transformation and cancer progression, highlighting the integrin adaptors as key players in the onset of tumorigenesis.

  • Targeting integrin adaptors by modulating their expression levels or their activity in different types of cancer has been proven to be effective for interfering with malignancy, making the integrin adaptors suitable targets for cancer therapy.

Abstract

Current evidence highlights the ability of adaptor (or scaffold) proteins to create signalling platforms that drive cellular transformation upon integrin-dependent adhesion and growth factor receptor activation. The understanding of the biological effects that are regulated by these adaptors in tumours might be crucial for the identification of new targets and the development of innovative therapeutic strategies for human cancer. In this Review we discuss the relevance of adaptor proteins in signalling that originates from integrin-mediated cell–extracellular matrix (ECM) adhesion and growth factor stimulation in the context of cell transformation and tumour progression. We specifically underline the contribution of p130 Crk-associated substrate (p130CAS; also known as BCAR1), neural precursor cell expressed, developmentally down-regulated 9 (NEDD9; also known as HEF1), CRK and the integrin-linked kinase (ILK)–pinch–parvin (IPP) complex to cancer, along with the more recently identified p140 Cas-associated protein (p140CAP; also known as SRCIN1).

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Figure 1: Main structural features and interactors of integrin adaptors.
Figure 2: p130 CAS and NEDD9 signalling.
Figure 3: The signalling platform formed by the IPP complex.
Figure 4: p140CAP regulation of intracellular signalling.

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Acknowledgements

This work was supported by grants of the AIRC, AICR, EU FP7 Metafight program, MIUR (PRIN and FIRB, Futuro in Ricerca), Progetto Alfieri, Regione Piemonte (Oncoprot, Druidi, PiStem and BioTher), Regione Piemonte Sanità to M.d.P.C.-L. is supported by the AICR.

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DATABASES

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fulvestrant

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Glossary

G3 index

In the classification of human breast cancer, grade 3 (G3) indicates that the cancer has spread to lymph nodes, regardless of its size.

Podosome

A type of ECM contact that is different from focal complexes and focal adhesions. It is built around an actin filament core, surrounded by a ring structure of integrin adhesive complexes.

Amoeboid movement

This movement is characterized by high speeds, a lack of stable polarity and an amorphous cell shape, and it is frequently exhibited by cancer cells. It does not require stable integrin-dependent adhesion for traction but depends on RHOA to increase actomyosin contractility and allow invasion in the absence of extracellular proteolysis.

Mesenchymal movement

The movement of cells with elongated morphology and a front-back polarity, with traction generated through integrin-dependent adhesion. This type of motility requires extracellular proteolysis for cell invasion and is thought to depend on RAC1.

Collective motility

The migration of cells as a cohesive group, a hallmark of tissue remodelling during wound repair and cancer invasion. It is characterized by cells moving as sheets, strands, clusters or ducts rather than individually.

Actin stress fibres

Self-assembling, structural components of the cytoskeleton that typically appear as long, thick actin bundles that span across the cell body and lie along the ventral surface. By binding to myosin, they produce traction forces and resting tension.

Cortical actin

A concentrated layer of actin filaments that lie longitudinally and roughly parallel to each other just beneath the plasma membrane.

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Cabodi, S., del Pilar Camacho-Leal, M., Di Stefano, P. et al. Integrin signalling adaptors: not only figurants in the cancer story. Nat Rev Cancer 10, 858–870 (2010). https://doi.org/10.1038/nrc2967

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