Keratin 8/18 modulation of protein kinase C-mediated integrin-dependent adhesion and migration of liver epithelial cells.
Keratins are intermediate filament (IF) proteins of epithelial cells, expressed as pairs in a lineage/differentiation manner. Hepatocyte and hepatoma cell IFs are made solely of keratins 8/18 (K8/K18), the hallmark of all simple epithelia. Cell attachment/spreading (adhesion) and migration involve the formation of focal adhesions at sites of integrin interactions with extracellular matrix, actin adaptors such as talin and vinculin, and signaling molecules such as focal adhesion kinase (FAK) and member(s) of the protein kinase C (PKC) family. Here, we identify the novel PKCdelta as mediator of the K8/K18 modulation of hepatoma cell adhesion and migration. We also demonstrate a K8/K18-dependent relationship between PKCdelta and FAK activation through an integrin/FAK-positive feedback loop, in correlation with a reduced FAK time residency at focal adhesions. Notably, a K8/K18 loss results to a time course modulation of the receptor of activated C-kinase-1, beta1-integrin, plectin, PKC, and c-Src complex formation. Although the K8/K18 modulation of hepatocyte adhesion also occurs through a PKC mediation, these differentiated epithelial cells exhibit minimal migrating ability, in link with marked differences in protein partner content and distribution. Together, these results uncover a key regulatory function for K8/K18 IFs in the PKC-mediated integrin/FAK-dependent adhesion and migration of simple epithelial cells.
Bordeleau
François
F
Centre de Recherche en Cancérologie and Département de Médecine de l'Université Laval, and Centre de Recherche du Centre Hospitalier Universitaire de Québec (CRCHUQ), Quebec City, QC, Canada.
Galarneau
Luc
L
Gilbert
Stéphane
S
Loranger
Anne
A
Marceau
Normand
N
D000199:Actins / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D016193:G1 Phase; D022781:Hepatocytes / Q000378:metabolism*; D019012:Integrin beta1 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D007381:Intermediate Filament Proteins / Q000378:metabolism; D053538:Keratin-18 / Q000378:metabolism; D053533:Keratin-8 / Q000378:metabolism; D007633:Keratins / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051190:Plectin / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism
D000199:Actins; D019012:Integrin beta1; D016023:Integrins; D007381:Intermediate Filament Proteins; D053538:Keratin-18; D053533:Keratin-8; D051190:Plectin; D011506:Proteins; D016596:Vinculin; D007633:Keratins; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D011493:Protein Kinase C