Keratins modulate hepatic cell adhesion, size and G1/S transition

Exp Cell Res. 2007 Jan 1;313(1):179-94. doi: 10.1016/j.yexcr.2006.10.007. Epub 2006 Oct 13.


Keratins (Ks) are the intermediate filament (IF) proteins of epithelial cells. Hepatocyte IFs are made solely of keratins 8 and 18 (K8/K18), the hallmark of all simple epithelia. While K8/K18 are essential for maintaining structural integrity, there is accumulating evidence indicating that they also exert non-mechanical functions. We have reported recently that K8/K18-free hepatocytes from K8-null mice are more sensitive to Fas-mediated apoptosis, in line with an increased Fas density at the cell surface and an altered c-Flip regulation of the anti-apoptotic ERK1/2 signaling pathway. In the present study, we show that K8-null hepatocytes attach more rapidly but spread more slowly on a fibronectin substratum and undergo a more efficient G1/S transition than wild-type hepatocytes. Moreover, plectin, an IF associated protein, receptor for activated C kinase 1 (RACK1), a plectin partner, and vinculin, a key component of focal adhesions, distribute differently in spreading K8-null hepatocytes. Cell seeding leads to no differential activation of ERK1/2 in WT versus K8-null hepatocytes, whereas a stronger Akt activation is detected in K8-null hepatocytes. Insulin stimulation also leads to a differential Akt activation, implying altered Akt signaling capacity as a result of the K8/K18 loss. In addition, a delayed autophosphorylation of FAK, a target for integrin beta1 signaling, was obtained in seeding K8-null hepatocytes. These alterations in cell cycle-related events in hepatocytes in primary culture are also found in a K8-knockdown H4-II-E-C3 rat hepatoma cell line. Besides, K8/K18-free cells are smaller and exhibit a reduced rate of protein synthesis. In addition, a distinctive cyclin interplay is observed in these K8/K18-free hepatic cells, namely a more efficient cyclin A-dependent G1/S phase transition. Furthermore, K8 re-expression in these cells, following transfer of a human K8 cDNA, restores proper cell size, spreading and growth. Together, these results suggest new interrelated signaling roles of K8/18 with plectin/RACK1 in the modulation of cell attachment/spreading, size/protein synthesis and G1/S transition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Size
  • Cells, Cultured
  • DNA Primers / genetics
  • Focal Adhesion Kinase 1 / metabolism
  • G1 Phase
  • Hepatocytes / cytology*
  • Hepatocytes / metabolism*
  • Humans
  • Integrin beta1 / metabolism
  • Keratin-18 / metabolism
  • Keratin-8 / deficiency
  • Keratin-8 / genetics
  • Keratin-8 / metabolism
  • Keratins / metabolism*
  • Mice
  • Mice, Knockout
  • Neuropeptides / metabolism
  • Plectin / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Receptors for Activated C Kinase
  • S Phase
  • Signal Transduction
  • Vinculin / metabolism


  • DNA Primers
  • Integrin beta1
  • Keratin-18
  • Keratin-8
  • Krt8 protein, mouse
  • Neuropeptides
  • Plectin
  • RACK1 protein, mouse
  • Receptors for Activated C Kinase
  • Vinculin
  • Keratins
  • Focal Adhesion Kinase 1
  • Ptk2 protein, mouse
  • Proto-Oncogene Proteins c-akt