Mer receptor tyrosine kinase signaling.: Prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation.
Mer receptor tyrosine kinase signaling.: Prevention of apoptosis and alteration of cytoskeletal architecture without stimulation or proliferation.
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DOI：
10.1074/jbc.m112086200
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发表时间：
2002-07-05
影响因子：
4.8
通讯作者：
Earp, HS
中科院分区：
文献类型：
--
作者：
Guttridge, KL;Luft, JC;Earp, HS
Mer是Axl/Mer/Tyro3受体酪氨酸激酶家族的一员，该家族的生理功能尚未明确。我们利用表皮生长因子受体（EGFR）细胞外、跨膜结构域和Mer细胞质结构域构建了Mer嵌合体。将Mer嵌合体稳定转染到白细胞介素3 （IL-3）依赖的小鼠32D细胞中，导致配体活化的表面受体酪氨酸自磷酸化，刺激细胞内信号传导，并显著减少IL-3戒断引起的细胞凋亡。然而，与其他多种异位表达受体酪氨酸激酶（包括全长EGFR或EGFR/Axl嵌合体）不同，Mer嵌合体不会刺激增殖。此外，与EGFR相反，Mer嵌合体激活在正常悬浮生长的32D细胞中诱导粘附和细胞变平。Mer嵌合体信号也阻断了il -3依赖的增殖，导致G(1)/S阻滞，视网膜母细胞瘤蛋白的去磷酸化和细胞过程的延长。与其他激动剂导致32D细胞缓慢（4-8天）依赖配体的分化不同，Mer和IL-3联合信号在最初24小时内导致分化形态和生长停止。因此，Mer嵌合体在不刺激生长的情况下阻止细胞凋亡，并产生细胞骨架改变；这一结果与大多数受体酪氨酸激酶产生的增殖信号是明显分开的。
Mer is a member of the Axl/Mer/Tyro3 receptor tyrosine kinase family, a family whose physiological function is not well defined. We constructed a Mer chimera using the epidermal growth factor receptor (EGFR) extracellular and transmembrane domains and the Mer cytoplasmic domain. Stable transfection of the Mer chimera into interleukin 3 (IL-3)-dependent murine 32D cells resulted in ligand-activable surface receptor that tyrosine autophosphorylated, stimulated intracellular signaling, and dramatically reduced apoptosis initiated by IL-3 withdrawal. However, unlike multiple other ectopically expressed receptor tyrosine kinases including full-length EGFR or an EGFR/Axl chimera, the Mer chimera did not stimulate proliferation. Moreover, and in contrast to EGFR, Mer chimera activation induced adherence and cell flattening in the normally suspension-growing 32D cells. The Mer chimera signal also blocked IL-3-dependent proliferation leading to G(1)/S arrest, dephosphorylation of retinoblastoma protein, and elongation of cellular processes. Unlike other agonists that lead to a slow (4-8 days) ligand-dependent differentiation of 32D cells, the combined Mer and IL-3 signal resulted in differentiated morphology and growth cessation in the first 24 h. Thus the Mer chimera blocks apoptosis without stimulating growth and produces cytoskeletal alterations; this outcome is clearly separable from the proliferative signal produced by most receptor tyrosine kinases.