Abstract
Epithelial cells form sheets and tubules in various epithelial organs and establish apicobasal polarity and asymmetric vesicle transport to provide functionality in these structures. However, the molecular mechanisms that allow epithelial cells to establish polarity are not clearly understood. Here, we present evidence that the kinase activity of the receptor tyrosine kinase for collagen, discoidin domain receptor 1 (DDR1), is required for efficient establishment of epithelial polarity, proper asymmetric protein secretion, and execution of morphogenic programs. Lack of DDR1 protein or inhibition of DDR1 kinase activity disturbed tubulogenesis, cystogenesis, and the establishment of epithelial polarity and caused defects in the polarized localization of membrane-type 1 matrix metalloproteinase (MT1-MMP), GP135, primary cilia, laminin, and the Golgi apparatus. Disturbed epithelial polarity and cystogenesis upon DDR1 inhibition was caused by excess ROCK (rho-associated, coiled-coil-containing protein kinase)-driven actomyosin contractility, and pharmacological inhibition of ROCK was sufficient to correct these defects. Our data indicate that a DDR1-ROCK signaling axis is essential for the efficient establishment of epithelial polarity.
Highlights
Epithelial tubules form important functional units in various epithelial organs and are composed of polarized epithelial cells
We have found that the default localization of membrane-type 1 matrix metalloproteinase (MT1-MMP) in polarized MDCK epithelial cells is at the apical surface, whereas cells under stimulation with hepatocyte growth factor (HGF) localize Membrane-type 1 matrix metalloproteinases (MT1MMP) to the basal side where it facilitates invasion (Weaver et al, 2014)
To confirm that HGF-induced changes in the apicobasal localization of MT1-MMP occur in live cells, we created MT1-MMP fused with a pH-sensitive GFP, superecliptic pHluorin (Miesenbock et al, 1998), in the ectodomain and mRFP-1 in the cytoplasmic domain (MT1F-pHluorin-RFP, Fig 1A, left)
Summary
Epithelial tubules form important functional units in various epithelial organs and are composed of polarized epithelial cells. Polarized epithelial cells establish polarity and divide the plasma membrane into apical, lateral, and basal membrane domains, allowing various molecules to be secreted to specific areas of the plasma membrane. Tubulogenesis results from coordination of fate determination of tip cells and follower cells, cell proliferation, cell adhesion to the ECM, ECM degradation, and cytoskeletal reorganization within the 3D environment. This coordination relies on epithelial polarity being established and maintained to achieve proper placement of functional molecules in the right area of the plasma membrane at the right time. The underlying molecular mechanism that drives this localization switch is unknown
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