Periostin induces intracellular cross-talk between kinases and hyaluronan in atrioventricular valvulogenesis.
Periostin (PN), a novel fasciclin-related matricellular protein, has been implicated in cardiac development and postnatal remodeling, but the mechanism remains unknown. We examined the role of PN in mediating intracellular kinase activation for atrioventricular valve morphogenesis using well defined explant cultures, gene transfection systems, and Western blotting. The results show that valve progenitor (cushion) cells secrete PN into the extracellular matrix, where it can bind to INTEGRINs and activate INTEGRIN/focal adhesion kinase signaling pathways and downstream kinases, PI3K/AKT and ERK. Functional assays with prevalvular progenitor cells showed that activating these signaling pathways promoted adhesion, migration, and anti-apoptosis. Through activation of PI3K/ERK, PN directly enhanced collagen expression. Comparing PN-null to WT mice also revealed that expression of hyaluronan (HA) and activation of hyaluronan synthase-2 (Has2) are also enhanced upon PN/INTEGRIN/focal adhesion kinase-mediated activation of PI3K and/or ERK, an effect confirmed by the reduction of HA synthase-2 in PN-null mice. We also identified in valve progenitor cells a potential autocrine signaling feedback loop between PN and HA through PI3K and/or ERK. Finally, in a three-dimensional assay to simulate normal valve maturation in vitro, PN promoted collagen compaction in a kinase-dependent fashion. In summary, this study provides the first direct evidence that PN can act to stimulate a valvulogenic signaling pathway.
From the Department of Regenerative Medicine and Cell Biology.
Shibnath
S
Ghatak
Suniti
S
Misra
Russell A
RA
Norris
Ricardo A
RA
Moreno-Rodriguez
Stanley
S
Hoffman
Robert A
RA
Levine
Vincent C
VC
Hascall
Roger R
RR
Markwald
D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D002642:Chick Embryo; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D017353:Gene Deletion; D006351:Heart Valves / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction
D015815:Cell Adhesion Molecules; D016023:Integrins; C082838:Postn protein, mouse; D006820:Hyaluronic Acid; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt
Atrioventricular Valve; Cd44; Cell Adhesion; Cell Migration; Collagen; Hyaluronate; Integrins; Intracellular Kinase Signaling; Periostin; Prevalvular Cushion Cells