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Originally published as MBC in Press, 10.1091/mbc.E05-09-0871 on October 26, 2005

Vol. 17, Issue 1, 345-356, January 2006

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Type I Collagen Structure Regulates Cell Morphology and EGF Signaling in Primary Rat Hepatocytes through cAMP-dependent Protein Kinase A

John Fassett *, Diane Tobolt {dagger}, and Linda K. Hansen {ddagger}

Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455

Submitted September 20, 2005; Accepted October 19, 2005
Monitoring Editor: Richard Assoian

Adhesion to type 1 collagen elicits different responses dependent on whether the collagen is in fibrillar (gel) or monomeric form (film). Hepatocytes adherent to collagen film spread and proliferate, whereas those adherent to collagen gel remain rounded and growth arrested. To explore the role of potential intracellular inhibitory signals responsible for collagen gel-mediated growth arrest, cAMP-dependent protein kinase A (PKA) was examined in hepatocytes adherent to collagen film or gel. PKA activity was higher in hepatocytes on collagen gel than on film during G1 of the hepatocyte cell cycle. Inhibition of PKA using H89 increased cell spreading on collagen gel in an EGF-dependent manner, whereas activation of PKA using 8-Br-cAMP decreased cell spreading on collagen film. PKA inhibition also restored ERK activation, cyclin D1 expression and G1-S progression on collagen gel, but had no effect on cells adherent to collagen film. Analysis of EGF receptor phosphorylation revealed that adhesion to collagen gel alters tyrosine phosphorylation of the EGF receptor, leading to reduced phosphorylation of tyrosine residue 845, which was increased by inhibition of PKA. These results demonstrate that fibrillar type 1 collagen can actively disrupt cell cycle progression by inhibiting specific signals from the EGF receptor through a PKA-dependent pathway.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E05-09-0871) on October 26, 2005.

* Present address: Department of Medicine, University of Minnesota, Minneapolis, MN 55455

{dagger} Present address: Personal Laboratory Services, PMB 226, 1730 New Brighton Blvd., Minneapolis, MN 55413

{ddagger} Present address: AppTec Laboratory Services, 2540 Executive Drive, St. Paul, MN 55120.

Address correspondence to: Linda K. Hansen (linda.hansen{at}apptec-usa.com).




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