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Vol. 10, Issue 7, 2441-2459, July 1999

Rho-dependent Regulation of Cell Spreading by the Tetraspan Membrane Protein Gas3/PMP22

Claudio Brancolini,^* Stefania Marzinotto,^* Paolo Edomi,^*§ Elena Agostoni,^* Carla Fiorentini, Hans Werner Müller,^¶ and Claudio Schneider^*

 ^*Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie, 34142 Trieste, Italy;  Dipartimento di Scienze e Tecnologie Biomediche, Sezione di Biologia-Universitá di Udine, 33100 Udine, Italy;  ^§Dipartimento di Biologia Universitá di Trieste, 34100 Trieste, Italy;  Dipartimento di Ultrastruttura, Istituto Superiore di Sanitá, 00161 Rome, Italy; and  ^¶Molecular Neurobiology Laboratory, Department of Neurology, Heinrich-Heine-University, 40225 Dusseldorf, Germany

Gas3/PMP22 plays a crucial role in regulating myelin formation and maintenance, and different genetic alterations in gas3/PMP22 are responsible for a set of human peripheral neuropathies. We have previously demonstrated that Gas3/PMP22 could regulate susceptibility to apoptosis in NIH3T3 cells but not in REF 52 cells. In this report we demonstrate that when the apoptotic response triggered by gas3/PMP22 was counteracted by Bcl-2 coexpression, morphological changes were observed. Time-lapse analysis confirmed that Gas3/PMP22 can modulate cell spreading, and this effect was strengthened after inhibition of phosphoinositide 3-kinase. Using the active form of the small GTPase RhoA, we have been able to dissect the different Gas3/PMP22 biological activities. RhoA counteracted the Gas3/PMP22-dependent morphological response but was unable to neutralize the apoptotic response. Treatment of NIH3T3 cells with cytotoxic necrotizing factor 1, which activates endogenous Rho, also counteracted Gas3/PMP22-mediated cell shape and spreading changes. Treatment of REF 52 cells, which are unresponsive to Gas3/PMP22 overexpression, with the C3 exoenzyme, inhibiting Rho activity, renders REF 52 cells responsive to Gas3/PMP22 overexpression for cell shape and spreading changes. Finally, assembly of stress fibers and focal adhesions complexes, in response to lysophosphatidic acid-induced endogenous Rho activation, was impaired in Gas3/PMP22-overexpressing cells. We hypothesize that cell shape and spreading regulated by Gas3/PMP22 through the Rho GTPase might have an important role during Schwann cells differentiation and myelinization.

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   Corresponding author. E-mail address: brancoli{at}sci.area.trieste.it.

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Molecular Biology of the Cell
Vol. 10, 2441-2459, July 1999
Copyright © 1999 by The American Society for Cell Biology

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