Periostin Induces Intracellular Cross-talk between Kinases and Hyaluronan in Atrioventricular Valvulogenesis

Abstract

Background: Periostin-null mice exhibit a myxomatous atrioventricular valve phenotype. We propose two mechanisms as follows: periostin binds to collagen and links it to cell-surface receptors; periostin/␤-INTEGRIN signaling promotes valve morphogenesis. Results: Periostin/␤-INTEGRINs/focal adhesion kinase/PI3K/ERK signals promote hyaluronan synthase-2 activation, matrix remodeling, and valve progenitor cell survival/differentiation. Conclusion:The phenotype of periostin-null valves is consistent with a role for PN cell signaling through INTEGRIN receptors. Significance: Periostin is a valvulogenic signaling morphogen.

Congenital Heart Disease: In Search of Remedial Etiologies

“…Another plus for interactive signaling hubs is their potential to reveal a new or unexpected "spoke" whereby genetic, protein, or biochemical connections to signaling pathways are not readily apparent or known, e.g., hyaluronan synthetase 2 (Has2). As shown by Misra et al [6], Has2 is activated by nodal kinases that are regulated by periostin-integrin-linked signaling [6]. Phosphorylation of Has2 leads to secretion of hyaluronan (HA) (Fig.…”

“…Binding of HA to CD44 activates some of the same kinases also activated by periostin-integrin signaling, thereby triggering positive feedback loops that can amplify or sustain shared biological effects of periostin including formation, migration, and survival of progenitor valvuloseptal mesenchyme as well as a positive feedback on the secretion of periostin itself ( Fig. 5.1) [6,11]. CD44 signaling also appears to be part of a signaling complex revealed by immunoprecipitation that is required for periostin to activate another candidate signaling hub -filamin A ( Fig.…”

“…5.2). [6], periostin binding to integrin induces phosphorylation of p-FAK (a nodal kinase) which, in turn, activates different signaling pathways, p-AKT/PI3K and/or p-Erk, each with distinct biological activities; e.g., p-AKT/PI3K promotes hyaluronan (HA) secretion and enhances periostin expression, whereas Erk activates collagen secretion and survival (anti-apoptotic) mechanisms…”

“…As indicated in Fig. 5.1, intracellular signaling kinases (and small regulatory GTPases) are the direct and indirect downstream targets of growth factors (e.g., TGFβ and BMP 2&4) that are normally secreted by the embryonic endocardium or myocardium [5], or in the case of extracellular ligands like matricellular proteins (periostin, the CCN family), they are secreted by the mesenchymal progenitor cells of valves and connective septa which are derived from both endocardium and epicardium [6]. In the case of matricellular and other extracellular proteins ( Fig.…”

“…As proof of concept, we prepared a lentivirus periostin-silencing (shRNA) vector directed against the 3 0 end of the periostin transcript that was shown to block periostin protein expression (>95 %) in vitro [6,19]. These silencing or empty control vectors were injected directly into the bone marrow minutes prior to an acute myocardial "cryoinjury" administered by a liquid nitrogen cooled microprobe directly to the left ventricle of anesthetized mice.…”