Miura Grant I, Buglino John, Alvarado Diego, Lemmon Mark A, Resh Marilyn D, Treisman Jessica E
Department of Cell Biology, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Dev Cell. 2006 Feb;10(2):167-76. doi: 10.1016/j.devcel.2005.11.017.
Lipid modifications such as palmitoylation or myristoylation target intracellular proteins to cell membranes. Secreted ligands of the Hedgehog and Wnt families are also palmitoylated; this modification, which requires the related transmembrane acyltransferases Rasp and Porcupine, can enhance their secretion, transport, or activity. We show here that rasp is also essential for the developmental functions of Spitz, a ligand for the Drosophila epidermal growth factor receptor (EGFR). In cultured cells, Rasp promotes palmitate addition to the N-terminal cysteine residue of Spitz, and this cysteine is required for Spitz activity in vivo. Palmitoylation reduces Spitz secretion and enhances its plasma membrane association, but does not alter its ability to activate the EGFR in vitro. In vivo, overexpressed unpalmitoylated Spitz has an increased range of action but reduced activity. These data suggest a role for palmitoylation in restricting Spitz diffusion, allowing its local concentration to reach the threshold required for biological function.
诸如棕榈酰化或肉豆蔻酰化之类的脂质修饰可将细胞内蛋白质靶向至细胞膜。刺猬蛋白（Hedgehog）家族和Wnt家族的分泌配体也会发生棕榈酰化；这种修饰需要相关的跨膜酰基转移酶Rasp和豪猪蛋白（Porcupine），它可以增强这些配体的分泌、运输或活性。我们在此表明，Rasp对于果蝇表皮生长因子受体（EGFR）的配体Spitz的发育功能也至关重要。在培养细胞中，Rasp促进棕榈酸添加到Spitz的N端半胱氨酸残基上，并且该半胱氨酸是Spitz在体内发挥活性所必需的。棕榈酰化减少了Spitz的分泌并增强了其与质膜的结合，但在体外并未改变其激活EGFR的能力。在体内，过表达的未棕榈酰化的Spitz作用范围增加但活性降低。这些数据表明棕榈酰化在限制Spitz扩散方面发挥作用，使其局部浓度能够达到生物学功能所需的阈值。
