Tyro3 and Axl, two members of the TAM family of receptor tyrosine kinases, play important regulatory roles in a variety of tissues, including the central nervous, reproductive, immune, and vascular systems. We have found that expression of Tyro3 and Axl on PC12 cells is upregulated by nerve growth factor (NGF). PI3K inhibitor LY294002, which is known to inhibit NGF-induced PC12 differentiation, blocked up-regulation of Tyro3 and Axl. NGF regulates Tyro3 and Axl expression by activating their transcription. Both Tyro3 and Axl were associated with the NGF receptor, and protected PC12 cells from stress or toxin-induced cell death. Gas6, a common ligand for both Tyro3 and Axl, was able to replace NGF to support PC12 growth in serum-free medium, and to prevent cell death following serum deprivation. In summary, both Tyro3 and Axl receptors are upregulated by NGF on the differentiating PC12, where they collaborate with TrkA to support neuronal differentiation and survival. (C) 2008 Elsevier Inc. All rights reserved.