Abstract
Heparin-binding EGF-like growth factor (HB-EGF) is first synthesized as a membrane-anchored form (proHB-EGF), and its soluble form (sHB-EGF) is released by ectodomain shedding from proHB-EGF. To examine the significance of proHB-EGF processing in vivo, we generated mutant mice by targeted gene replacement, expressing either an uncleavable form (HBuc) or a transmembrane domain-truncated form (HBdeltatm) of the molecule. HB(uc/uc) mice developed severe heart failure and enlarged heart valves, phenotypes similar to those in proHB-EGF null mice. On the other hand, mice carrying HBdeltatm exhibited severe hyperplasia in both skin and heart. These results indicate that ectodomain shedding of proHB-EGF is essential for HB-EGF function in vivo, and that this process requires strict control.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Surface Extensions / genetics
-
Cell Surface Extensions / metabolism
-
Epidermal Growth Factor / deficiency*
-
Epidermal Growth Factor / genetics
-
Gene Targeting
-
Heart Defects, Congenital / genetics*
-
Heart Defects, Congenital / metabolism
-
Heart Defects, Congenital / pathology
-
Heart Valves / abnormalities
-
Heart Valves / pathology
-
Heparin-binding EGF-like Growth Factor
-
Hyperplasia / genetics*
-
Hyperplasia / metabolism
-
Hyperplasia / pathology
-
Intercellular Signaling Peptides and Proteins
-
Mice
-
Mice, Mutant Strains
-
Mutation / genetics
-
Protein Processing, Post-Translational / genetics
-
Protein Structure, Tertiary / genetics
-
Skin Abnormalities / genetics*
-
Skin Abnormalities / metabolism
-
Skin Abnormalities / pathology
-
Solubility
Substances
-
Hbegf protein, mouse
-
Heparin-binding EGF-like Growth Factor
-
Intercellular Signaling Peptides and Proteins
-
Epidermal Growth Factor