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Integrin ?6 and EGFR signaling converge at mechanosensitive calpain 2.

ABSTRACT: Cells sense and respond to mechanical cues from the extracellular matrix (ECM) via integrins. ECM stiffness is known to enhance integrin clustering and response to epidermal growth factor (EGF), but we lack information on when or if these mechanosensitive growth factor receptors and integrins converge intracellularly. Towards closing this knowledge gap, we combined a biomaterial platform with transcriptomics, molecular biology, and functional assays to link integrin-mediated mechanosensing and epidermal growth factor receptor (EGFR) signaling. We found that high integrin ?6 expression controlled breast cancer cell adhesion and motility on soft, laminin-coated substrates, and this mimicked the response of cells to EGF stimulation. The mechanisms that drove both mechanosensitive cell adhesion and motility converged on calpain 2, an intracellular protease important for talin cleavage and focal adhesion turnover. EGF stimulation enhanced adhesion and motility on soft substrates, but required integrin ?6 and calpain 2 signaling. In sum, we identified a new role for integrin ?6 mechanosensing in breast cancer, wherein cell adhesion to laminin on soft substrates mimicked EGF stimulation. We identified calpain 2, downstream of both integrin ?6 engagement and EGFR phosphorylation, as a common intracellular signaling node, and implicate integrin ?6 and calpain 2 as potential targets to inhibit the migration of cancer cells in stiff tumor environments.

SUBMITTER: Schwartz AD

PROVIDER: S-EPMC6211197 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Integrin α<sub>6</sub> and EGFR signaling converge at mechanosensitive calpain 2.

Schwartz A D AD Hall C L CL Barney L E LE Babbitt C C CC Peyton S R SR

Biomaterials 20180602

Cells sense and respond to mechanical cues from the extracellular matrix (ECM) via integrins. ECM stiffness is known to enhance integrin clustering and response to epidermal growth factor (EGF), but we lack information on when or if these mechanosensitive growth factor receptors and integrins converge intracellularly. Towards closing this knowledge gap, we combined a biomaterial platform with transcriptomics, molecular biology, and functional assays to link integrin-mediated mechanosensing and e ...[more]

PMID: 29909039

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Project description:Previous studies show that both activin and Bmp4 act as crucial mesenchymal odontogenic signals during early tooth development. Remarkably, mice lacking activin-?A ( Inhba-/-) and mice with neural crest-specific inactivation of Bmp4 ( Bmp4ncko/ncko) both exhibit bud-stage developmental arrest of the mandibular molar tooth germs while their maxillary molar tooth germs completed morphogenesis. In this study, we found that, whereas expression of Inhba and Bmp4 in the developing tooth mesenchyme is independent of each other, Bmp4ncko/nckoInhba-/- compound mutant mice exhibit early developmental arrest of all tooth germs. Moreover, genetic inactivation of Osr2, a negative regulator of the odontogenic function of the Bmp4-Msx1 signaling pathway, rescues mandibular molar morphogenesis in Inhba-/- embryos. We recently reported that Osr2 and the Bmp4-Msx1 pathway control the bud-to-cap transition of tooth morphogenesis through antagonistic regulation of expression of secreted Wnt antagonists, including Dkk2 and Sfrp2, in the developing tooth mesenchyme. We show here that expression of Dkk2 messenger RNAs was significantly upregulated and expanded into the tooth bud mesenchyme in Inhba-/- embryos in comparison with wild-type littermates. Furthermore, in utero treatment with either lithium chloride, an agonist of canonical Wnt signaling, or the DKK inhibitor IIIC3a rescued mandibular molar tooth morphogenesis in Inhba-/- embryos. Together with our finding that the developing mandibular molar tooth bud mesenchyme expresses significantly higher levels of Dkk2 than the developing maxillary molar tooth mesenchyme, these data indicate that Bmp4 and activin signaling pathways converge on activation of the Wnt signaling pathway to promote tooth morphogenesis through the bud-to-cap transition and that the differential effects of loss of activin or Bmp4 signaling on maxillary and mandibular molar tooth morphogenesis are mainly due to the differential expression of Wnt antagonists, particularly Dkk2, in the maxillary and mandibular tooth mesenchyme.

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Dataset Information

Integrin ?6 and EGFR signaling converge at mechanosensitive calpain 2.

Publications

Integrin α<sub>6</sub> and EGFR signaling converge at mechanosensitive calpain 2.

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