LPA and NRG‐1b synergistically promote proliferation and migration of wild‐type and neoplastic Schwann cells via an ERRFI1‐dependent mechanism

Abstract

In some cell types, lysophosphatidic acid (LPA)‐induced proliferation and migration requires transactivation of the EGF receptor (erbB1). This led us to hypothesize that LPA stimulates the proliferation and migration of normal and neoplastic Schwann cells and does so via a mechanism involving the EGFR‐related NRG‐1 receptors erbB2, 3 and/or 4. We have found that LPA stimulates the proliferation and migration of wild‐type Schwann cells and malignant peripheral nerve sheath tumor (MPNST) cells in a concentration‐dependent manner. Co‐stimulation of Schwann cells with NRG‐1β and LPA increases mitogenesis to a greater extent than the combined effects of each factor alone, indicating that LPA and NRG‐1β synergistically enhance proliferation of these glia. Further, LPA‐induced Schwann cell migration is ablated by treatment with the erbB kinase inhibitor PD168393 or GM6001, a MMP inhibitor which blocks the release of soluble NRG‐1. Microarray analyses also show that LPA represses Schwann cell expression of the pan‐erbB inhibitor Erffi1, thereby potentially enhancing erbB action. These findings suggest that LPA stimulates Schwann cell proliferation and migration synergistically with NRG‐1β and does so via a previously unknown mechanism that involves modulation of Erffi1 expression. Funded by R01 NS048353 and CA122804.