Lax Irit, Wong Andy, Lamothe Betty, Lee Arnold, Frost Adam, Hawes Jessica, Schlessinger Joseph
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
Mol Cell. 2002 Oct;10(4):709-19. doi: 10.1016/s1097-2765(02)00689-5.
The docking protein FRS2alpha functions as a major mediator of signaling by FGF and NGF receptors. Here we demonstrate that, in addition to tyrosine phosphorylation, FRS2alpha is phosphorylated by MAP kinase on multiple threonine residues in response to FGF stimulation or by insulin, EGF, and PDGF, extracellular stimuli that do not induce tyrosine phosphorylation of FRS2alpha. Prevention of FRS2alpha threonine phosphorylation results in constitutive tyrosine phosphorylation of FRS2alpha in unstimulated cells and enhanced tyrosine phosphorylation of FRS2alpha, MAPK stimulation, cell migration, and proliferation in FGF-stimulated cells. Expression of an FRS2alpha mutant deficient in MAPK phosphorylation sites induces anchorage-independent cell growth and colony formation in soft agar. These experiments reveal a novel MAPK-mediated, negative feedback mechanism for control of signaling pathways that are dependent on FRS2 and a mechanism for heterologous control of signaling via FGF receptors.
对接蛋白FRS2α作为FGF和NGF受体信号传导的主要介质。我们在此证明，除酪氨酸磷酸化外，FRS2α在响应FGF刺激时或通过胰岛素、EGF和PDGF（这些细胞外刺激不会诱导FRS2α的酪氨酸磷酸化），在多个苏氨酸残基上被MAP激酶磷酸化。阻止FRS2α苏氨酸磷酸化会导致未刺激细胞中FRS2α的组成型酪氨酸磷酸化，并增强FGF刺激细胞中FRS2α的酪氨酸磷酸化、MAPK刺激、细胞迁移和增殖。缺乏MAPK磷酸化位点的FRS2α突变体的表达会诱导软琼脂中不依赖贴壁的细胞生长和集落形成。这些实验揭示了一种新的MAPK介导的负反馈机制，用于控制依赖FRS2的信号通路，以及一种通过FGF受体进行信号异源控制的机制。
