3254 | H.-J. Park et al. Molecular Biology of the Cell MBoC | ARTICLE The TAM-family receptor Mer mediates

ABSTRACT The TAM receptor protein tyrosine kinases Tyro3, Axl, and Mer play important roles in macrophage function. We investigated the roles of the TAM receptors in mediating the induction of hepatocyte growth factor (HGF) during the interaction of macrophages with apoptotic cells. Mer-specific neutralizing antibody, small interfering RNA (siRNA), and a re-combinant Mer protein (Mer/Fc) inhibited HGF mRNA and protein expression, as well as ac-tivation of RhoA, Akt, and specific mitogen-activated protein (MAP) kinases in response to apoptotic cells. Inhibition of Axl or Tyro3 with specific antibodies, siRNA, or Fc-fusion proteins did not prevent apoptotic cell–induced HGF mRNA and protein expression and did not in-hibit activation of the postreceptor signaling molecules RhoA and certain MAP kinases, in-cluding extracellular signal-regulated protein kinase and c-Jun NH2-terminal kinase. However, Axl- and Tyro3-specific blockers did inhibit the activation of Akt and p38 MAP kinase in re-sponse to apoptotic cells. In addition, none of the TAM receptors mediated the effects of apoptotic cells on transforming growth factor-β or epidermal growth factor mRNA expres-sion. However, they were involved in the induction of vascular endothelial growth factor mRNA expression. Our data provide evidence that when macrophages interact with apop-totic cells, only Mer of the TAM-family receptors is responsible for mediating transcriptional HGF production through a RhoA-dependent pathway