Epithelial cell kinase-B61: an autocrine loop modulating intestinal epithelial migration and barrier function.
Epithelial cell kinase (Eck) is a member of a large family of receptor tyrosine kinases whose functions remain largely unknown. Expression and regulation of Eck and its cognate ligand B61 were analyzed in the human colonic adenocarcinoma cell line Caco-2. Immunocytochemical staining demonstrated coexpression of Eck and B61 in the same cells, suggestive of an autocrine loop. Eck levels were maximal in preconfluent cells. In contrast, B61 levels were barely detectable in preconfluent cells and increased progressively after the cells reached confluence. Caco-2 cells cultured in the presence of added B61 showed a significant reduction in the levels of dipeptidyl peptidase and sucrase-isomaltase mRNA, markers of Caco-2 cell differentiation. Cytokines interleukin-1beta (IL-1beta), basic fibroblast growth factor, IL-2, epidermal growth factor, and transforming growth factor-beta modulated steady-state levels of Eck and B61 mRNA and regulated Eck activation as assessed by tyrosine phosphorylation. Functionally, stimulation of Eck by B61 resulted in increased proliferation, enhanced barrier function, and enhanced restitution of injured epithelial monolayers. These results suggest that the Eck-B61 interaction, a target of regulatory peptides, plays a role in intestinal epithelial cell development, migration, and barrier function, contributing to homeostasis and preservation of continuity of the epithelial barrier.
Rosenberg
I M
IM
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
Göke
M
M
Kanai
M
M
Reinecker
H C
HC
Podolsky
D K
DK
D000230:Adenocarcinoma; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms; D016207:Cytokines / Q000494:pharmacology*; D017931:DNA Primers; D036382:Ephrin-A1; D004815:Epidermal Growth Factor / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000502:physiology*; D008565:Membrane Proteins / Q000096:biosynthesis*; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D036104:Receptor, EphA2; D011994:Recombinant Proteins / Q000494:pharmacology; D013552:Swine; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D016207:Cytokines; D017931:DNA Primers; D036382:Ephrin-A1; D006133:Growth Substances; D007375:Interleukin-1; D007378:Interleukins; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016222:Fibroblast Growth Factor 2; D016220:Fibroblast Growth Factor 1; D004815:Epidermal Growth Factor; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases; D036104:Receptor, EphA2