Oncostatin M regulates membrane traffic and stimulates bile canalicular membrane biogenesis in HepG2 cells

Abstract

Hepatocytes are the major epithelial cells of the liver and they display membrane polarity: the sinusoidal membrane representing the basolateral surface, while the bile canalicular membrane is typical of the apical membrane. In polarized HepG2 cells an endosomal organelle, SAC, fulfills a prominent role in the biogenesis of the canalicular membrane, reflected by its ability to sort and redistribute apical and basolateral sphingolipids. Here we show that SAC appears to be a crucial target for a cytokine‐induced signal transduction pathway, which stimulates membrane transport exiting from this compartment promoting apical membrane biogenesis. Thus, oncostatin M, an IL‐6‐type cytokine, stimulates membrane polarity development in HepG2 cells via the gp130 receptor unit, which activates a protein kinase A‐dependent and sphingomyelin‐marked membrane transport pathway from SAC to the apical membrane. To exert its signal transducing function, gp130 is recruited into detergent‐resistant membrane microdomains at the basolateral membrane. These data provide a clue for a molecular mechanism that couples the biogenesis of an apical plasma membrane domain to the regulation of intracellular transport in response to an extracellular, basolaterally localized stimulus.

Oncostatin M-stimulated Apical Plasma Membrane Biogenesis Requires p27Kip1-Regulated Cell Cycle Dynamics

“…Indeed, we have previously shown that OSM activates a vesicular membrane trafficking pathway from SAC to the apical PM, which is dependent on cAMP/PKA activity (van der Wouden et al, 2002). Importantly, activation of this OSM-cAMP/PKA-regulated pathway is crucial for apical PM biogenesis in HepG2 cells (van der Wouden et al, 2002).…”

“…In addition, OSM induces adherens junction formation by altering the subcellular localization of adherens junction components, including E-cadherin and catenins (Matsui et al, 2002). In human fetal hepatocytes as well as in welldifferentiated human hepatic HepG2 cells, OSM stimulates the development of apical bile canalicular plasma membrane (PM) domains (Lazaro et al, 2003;van der Wouden et al, 2002), which requires the activation of a gp130-mediated signaling cascade and endogenous protein kinase A (PKA) activity (van der Wouden et al, 2002). Although the molecular mechanisms that underlie apicalization of the cell surface in hepatocytes are poorly understood, the de novo reorganization of the lateral PM after the establishment of E-cadherin-dependent cell-cell adhesion, mediated by cytoskeleton rearrangements and the polarized sorting and trafficking of proteins and lipids, plays a crucial role.…”

“…Moreover, polarized membrane traffic from SAC is also important for the de novo biogenesis of apical PM domains (van IJzendoorn and Hoekstra, 2000), triggered by extracellular stimuli, including OSM (van der Wouden et al, 2002) and those that elicit cAMP/PKA signaling cascades (Zegers and Hoekstra, 1997). Indeed, we have previously shown that OSM activates a vesicular membrane trafficking pathway from SAC to the apical PM, which is dependent on cAMP/PKA activity (van der Wouden et al, 2002). Importantly, activation of this OSM-cAMP/PKA-regulated pathway is crucial for apical PM biogenesis in HepG2 cells (van der Wouden et al, 2002).…”

“…The SAC plays a prominent role in the polarized delivery of proteins and lipids, and thus in maintaining cell surface polarity (Ihrke et al, 1998; van IJzendoorn and Hoekstra, 1999a,b;Rahner et al, 2000; van IJzendoorn and Mostov, 2000). Moreover, polarized membrane traffic from SAC is also important for the de novo biogenesis of apical PM domains (van IJzendoorn and Hoekstra, 2000), triggered by extracellular stimuli, including OSM (van der Wouden et al, 2002) and those that elicit cAMP/PKA signaling cascades (Zegers and Hoekstra, 1997). Indeed, we have previously shown that OSM activates a vesicular membrane trafficking pathway from SAC to the apical PM, which is dependent on cAMP/PKA activity (van der Wouden et al, 2002).…”

“…Indeed, we have previously shown that OSM activates a vesicular membrane trafficking pathway from SAC to the apical PM, which is dependent on cAMP/PKA activity (van der Wouden et al, 2002). Importantly, activation of this OSM-cAMP/PKA-regulated pathway is crucial for apical PM biogenesis in HepG2 cells (van der Wouden et al, 2002).The pronounced effects of OSM on cell cycle progression, membrane traffic, and cell polarity prompted us to investigate the functional relationship between these events to obtain better insight into molecular mechanisms that control the establishment of apical surface domains in conjunction with cell cycle control. …”